WO2007142217A1

WO2007142217A1 - 1-phenylpyridone derivative

Info

Publication number: WO2007142217A1
Application number: PCT/JP2007/061333
Authority: WO
Inventors: Hiroyuki Kishino; Yuji Haga; Sayaka Mizutani; Minoru Moriya; Norikazu Otake
Original assignee: Banyu Pharmaceutical Co., Ltd.
Priority date: 2006-06-07
Filing date: 2007-06-05
Publication date: 2007-12-13

Abstract

Disclosed is a compound represented by the formula (I) which can be used as an active ingredient: (I) wherein Az represents an azetidinyl group which may have a substituent; L represents a single bond or a C1-C2 alkylene group which may optionally have a substituent; and Ar represents a phenyl group which may optionally have a substituent or a pyridyl group which may optionally have a substituent. The compound is useful as an antagonist for a melanin-concentrating hormone receptor and is therefore useful as a pharmaceutical agent for a central nervous system disease, a cardiovascular disease or a metabolic disease.

Description

Specification

1-phenylbilidone derivatives

Technical field

[0001] The present invention relates to a novel 1-furubiridone derivative. The derivative acts as a melanin aggregation hormone receptor antagonist and is used as a preventive or therapeutic agent for various cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, respiratory diseases, gastrointestinal diseases and the like. Useful

Background art

[0002] Melanin Concentrating Hormone (hereinafter referred to as "MCH") is a cyclic peptide hormone Z neuropeptide that was first isolated from the pituitary gland by Kawauchi et al. [Nature, Vol. 305, 321 (1983)]. In fish, it is known to be functionally antagonized by melanocyte-stimulating hormone, causing aggregation of melanin granules in melanophores and contributing to changes in body color [International Review of Cytology, Vol. 126, 1 (1991); Trends in Endocrinology and Metabolis m, Vol. 5, 120 (1994)]. In mammals, the cell body of MCH-containing euron is located in the lateral hypothalamic area and indeterminate zone, but its nerve fibers are projected to a very wide area in the brain [The Journal of Comparative Neurology, Vol. 319, 218 (1992)], MCH is thought to be responsible for various central functions in the body.

[0003] The hypothalamic lateral cortex has long been known as a feeding center, and in recent years, much molecular biological 'pharmacological knowledge has been accumulated that suggests the involvement of MCH in energy homeostasis control. ing. That is, it has been reported that mRNA expression of MCH precursor is increased in the brain of obZob mice, dbZdb mice, AyZa mice, Zucker fatty rats and fasted mice, which are genetic obesity model animals [Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998); Biochemical and Biophysical Research Communications, Vol. 268, 88 (2000); Molecular Brain Research, Vol. 92, 43 (2001) reference]. [0004] Increased feeding was observed when MCH was administered acutely into the rat ventricle [Nature, Vol. 380, 243 (1996)], and chronic administration caused obesity with overeating [Proceedings of the National Academy of Sciences of the Unite a States of America, Vol. 99, 3240 (2002)]. In addition, mice lacking the MCH precursor gene showed lower food intake and higher oxygen consumption per body weight than wild-type mice, and low body weight due to decreased body fat was observed [ Nature, Vol. 396, 670 (1 998)].

[0005] In contrast, transgenic mice overexpressing MCH precursors exhibit hyperphagia with hyperphagia and insulin resistance [The Journal of Clinical Investigation, Vol. 107, 379 (2001)] ₀ The results suggest that MCH is an important factor in the formation of obesity, and that it is involved in metabolic disorders and respiratory diseases in which obesity is also a risk factor. In addition, MCH is known to cause anxiety, acupuncture, memory 'learning, diuresis, sodium / potassium excretion, oxytocin secretion, and reproductive' sexual function [Peptides, Vol. 17 , 171 (1996); Peptides, Vol. 18, 1095 (1997); Pe ptides, Vol. 15, 757 (1994); Journal of Neuroendocrinology, Vol. 8, 57 (1996); Critical Reviews in Neurobiology, Vol. 8 , 221 (1994)].

[0006] MCH induces various pharmacological actions mainly through MCH receptors present in the central nervous system. There are at least two types of receptors known for MCH: type 1 receptors (MCH-1R or SLC-1) and type 2 receptors (MCH-2R or SLT)! Vol. 400, 261 (1999); Nature, Vol. 400, 265 (1999); Biochemical and Biophysical Research Communications, Vol. 261, 622 (1999); Nature Cell Biology, Vol. 1, 267 (1999); FEBS Letters , Vol. 457, 522 (1999); Biochemical and Biophysical Research Communications, vol. 283, 10 13 (2001); The Journal of Biological Chemistry, Vol. 276, 20125 (200 1); Proceedings of the National Academy of Sciences of the Unite d States of America, Vol. 98, 7564 (2001); Proceedings of the Natio nal Academy of Sciences of the United States of America, Vol. 9 8, 7576 (2001); The Journal of Biological Chemistry, Vol. 276 , 34664 (2001); Molecular Pharmacology, Vol. 60, 632 (2001)].

[0007] Among them, the pharmacological action observed in rodents is mainly induced through MCH-1R.

[See Genomics, Vol, 79, 785 (2002)]. Overeating and obesity are not observed even when MCH is chronically administered to MCH-1R gene-deficient mice. Therefore, it is known that energy metabolism control by MCH is induced through MCH-1R. Furthermore, MCH-1R deficiency is known to increase activity in mice [see Proceedings of the National Academy oi sciences oi the United states of America, Vol. 99, 3240 (2002)]. It is also strongly implicated in central diseases with abnormalities, such as attention deficit / hyperactivity disorder, schizophrenia depression [Molecular Medicine Today, Vol. 6, 43 (2000); Trends in Neuroscience, Vol, 24, 527 (2001)].

[0008] It has also been reported that autoantibodies against MCH-1R exist in the serum of patients with vitiligo vulgaris [see The Journal of Clinical Investigation, Vol, 109, 923 (20 02)]. Furthermore, the expression of MCH-1R in certain cancer cells has been reported. From the expression site of MCH and MCH-1R in vivo, MCH cancer, sleep awakening, drug dependence, gastrointestinal tract Involvement in diseases has also been suggested [Biochemical and Biophysical Research Communications, Vol. 289, 44 (2001); Neuroendocnnology, Vo 1. 61, 348 (1995); Endocrinology, Vol. 137, 561 (1996); Jounal of Comparative Neurology, Vol. 435, 26 (2001)].

[0009] The function of MCH is expressed by binding of MCH to the MCH receptor. Therefore, inhibition of MCH receptor binding can block the expression of MCH action. Therefore, substances that antagonize receptor binding to MCH are various diseases involving MCH, such as obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, and other metabolic diseases; Symptom, acute depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte disorders, etc .; for example, bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, integration Central and peripheral nervous system diseases such as ataxia, attention deficit / hyperactivity disorder, memory impairment, sleep disorder, cognitive impairment, motor impairment, sensory abnormalities, olfactory disturbance, morphine tolerance, drug addiction, alcoholism; Life such as infertility, premature birth, sexual dysfunction It is expected to be useful as a prophylactic or therapeutic agent for reproductive diseases; gastrointestinal tract diseases, respiratory diseases, cancer or skin pigmentation.

Patent Document 1 or 2 discloses compounds having an MCH receptor antagonistic action, but they do not have a pyridone ring.

[0011] In addition, Patent Document 3 discloses certain pyridone derivatives having P38 MAP kinase activity, but does not describe MCH receptor antagonism. Patent Document 4 discloses a wide range of compounds including the compound of the present invention. However, in this publication, there is no specific disclosure for specific compounds having a azetidinyl group! /.

Patent Document 1: PCT International Publication WO01Z21577 Pamphlet

Patent Document 2: PCT International Publication WO02Z02744 Pamphlet

Patent Document 3: PCT International Publication WO03Z68230 pamphlet

Patent Document 4: PCT International Publication WO05Z085200 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0012] As a result of intensive studies on compounds having an MCH receptor antagonistic activity, the present inventors have found that a specific pyridone derivative containing a azetidinyl group only has an MCH receptor antagonistic activity. In particular, the present inventors have found that it has an excellent anti-obesity action in vivo and has an excellent balance as a pharmaceutical, and has completed the present invention.

Means for solving the problem

[0013] That is, the present invention provides

(1) Formula (I)

[0014] [Chemical 1]

During, Az optionally has a substituent and may represent a azetidyl group, L represents a single bond or optionally a substituent, and may represent a C1-C2 alkylene group, provided that , When L is a single bond, L is not bonded at the 1- or 2-position of the azetidyl group, and when L is a L-alkylene group, L is not bonded at the 1-position of the azetidinyl group.

Ar may optionally have a substituent, may be a phenol group or may optionally have a substituent, and may represent a pyridyl group]

1 A phenyl bilidone derivative represented by: or a pharmaceutically acceptable salt thereof.

[0015] Furthermore, the present invention provides:

(2) an MCH receptor antagonist comprising a compound represented by formula (I) as an active ingredient,

(3) a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by formula (I), and

(4) Metabolic diseases, including obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, hepatitis, and cirrhosis, which contain the compound represented by formula (I) as an active ingredient; narrow Cardiomyopathy, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, and cardiovascular disease represented by electrolyte abnormalities; bulimia, affective disorder, depression, anxiety, epilepsy, delirium, Dementia, schizophrenia, attention deficit ・ hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormalities, olfactory disturbance, morphine tolerance, narcotic dependence and alcohol dependence Nervous system diseases; reproductive diseases represented by infertility, premature birth and sexual dysfunction; gastrointestinal diseases; respiratory diseases; preventive or therapeutic agents for cancer or skin pigmentation

,I will provide a.

[0016] Further, the present invention provides:

(5) A method for preventing or treating a disease caused by melanin-concentrating hormone, which comprises administering an effective amount of the compound represented by formula (I) to a mammal, particularly a human,

(6) Use of a compound represented by formula (I) for producing a prophylactic or therapeutic agent for a disease caused by melanin-concentrating hormone.

The invention's effect

[0017] The compound of the present invention has MCH-1R antagonism, and obesity, diabetes, Metabolic disorders such as abnormal secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina, acute, congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities Cardiovascular diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory Central and peripheral nervous system diseases such as abnormalities, olfactory disturbance, morphine tolerance, narcotic addiction, alcoholism, reproductive system diseases such as infertility, premature birth, sexual dysfunction, etc. It is useful as a prophylactic or therapeutic agent for cancer or skin pigmentation, particularly as a prophylactic or therapeutic agent for obesity.

Brief Description of Drawings

[0018] FIG. 1 is a graph showing the spontaneous food intake of mice up to 24 hours after oral administration of the compound of the present invention to mice with dietary obesity.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

In the present specification, the term “lower” means that the group or compound to which the word is attached has 6 or less carbon atoms, preferably 4 or less.

[0021] The "lower alkyl group" includes a C1-C6 linear or C3-C6 branched alkyl group, and specifically includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group. Group, n-butyl group, isobutyl group, sec butyl group, tert butyl group, n pentyl group, isopentyl group, neopentyl group, tert-amyl group, 1 methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group 1-ethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2, 2-dimethylbutyl group, 1-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group, 1-ethyl-1-methylpropyl group, etc. I'm glad. The C1-C4 alkyl group includes a C1-C4 straight chain or C3-C4 branched alkyl group.

[0022] "Lower cycloalkyl group" includes C3-C6 cycloalkyl groups, and specifically includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group. Group.

[0023] The "lower alkylene group" includes a C1-C6 linear or C3-C6 branched alkylene group, and specifically includes, for example, a methylene group, an ethylene group, a propylene group, a butylene. Group, pentylene group, hexylene group and the like. The C1-C2 alkylene group means an alkylene group having 1 or 2 carbon atoms in the main chain.

[0024] “optionally substituted, may be an azetidyl group”, “optionally substituted !, may be a C1-C2 alkylene group”, “optionally substituted. Examples of the substituent in the phenyl group or the pyridyl group optionally having a substituent include, for example, a halogen atom, a cyano group, a hydroxyl group, and optionally a fluorine atom. Alternatively, it may be substituted with a hydroxyl group, or a lower alkyl group, optionally substituted with a fluorine atom or a hydroxyl group, or a lower cycloalkyl group, optionally substituted with a fluorine atom. Lower alkyloxy group, lower alkyloxy lower alkyl group, lower alkyloxy carbonyl group, lower alkylcarbonyl group, lower alkylcarbonyloxy group, rubamoyloxy group, mono-lower alkyl group Examples thereof include rubamoyloxy group, di-lower alkylcarbamoyloxy group, lower alkylsulfol group, sulfamoyl group, mono-lower alkylsulfamoyl group, di-lower alkylsulfamoyl group, etc. The “C1-C2 alkylene group”, “phenyl group” or “pyridyl group” may be substituted by one or more of these substituents.

[0025] In the above definition of substituents, examples of the "halogen atom" include a fluorine atom, a chlorine atom, an iodine atom, and an iodine atom.

[0026] In the "lower alkyl group optionally substituted with a fluorine atom or a hydroxyl group", some or all of the hydrogen atoms of the lower alkyl group or the lower alkyl group are substituted with a fluorine atom or a hydroxyl group. Examples of the lower alkyl group substituted with a fluorine atom or a hydroxyl group include, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, 1, 2 —Difluoroethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group and the like can be mentioned.

[0027] The "lower cycloalkyl group optionally substituted with a fluorine atom or a hydroxyl group" may include a part of hydrogen atoms of the lower cycloalkyl group or the lower cycloalkyl group. Includes a lower cycloalkyl group which is entirely substituted with a fluorine atom or a hydroxyl group. Examples of the lower cycloalkyl group substituted with the latter fluorine atom or hydroxyl group include a fluorocyclopropyl group, Fluorocyclobutyl group, Fluorocyclopentyl group, Fluorocyclohexyl group, Difluorocyclopropyl group, 1,2-Difluorocyclopropyl group, Hydroxycyclopropyl group, Hydroxycyclobutyl group, Hydroxycyclopentyl group, Examples thereof include a hydroxycyclohexyl group and a 1,2-dihydroxycyclopropyl group.

The “lower alkyloxy group optionally substituted with a fluorine atom” includes a group in which a lower alkyl group or a lower alkyl group substituted with a fluorine atom is bonded to an oxygen atom. Specifically, examples of the lower alkyloxy group include a methoxy group, an ethoxy group, an n propyloxy group, an isopropyloxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, and an n-pentyloxy group. Examples of the substituted lower alkyloxy group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1,2-difluoroethoxy group, and the like.

[0029] The "lower alkyloxy lower alkyl group" is a lower alkyl group substituted with a lower alkyloxy group. Specifically, for example, a methoxymethyl group, an ethoxymethyl group, an n-propyloxymethyl group, isopropyl Examples include an oxymethyl group, a 1-methoxyethyl group, and a 2-methoxy group.

[0030] "Lower alkyloxycarbonyl group" is a group in which a lower alkyloxy group is bonded to a carbo group (one CO 2), and includes C1-C6 alkyloxycarbol groups, Specifically, for example, a methoxy carbo ol group, an ethoxy carbo ol group, an n propyloxy carbonyl group, an isopropyloxy carbo ol group, an n-butoxy carbo ol group, an isobutoxy carbo ol group, a tert Examples thereof include a butoxycarbonyl group and an n-pentyloxycarbonyl group.

The “lower alkylcarbonyl group” is a group in which a lower alkyl group is bonded to a carbo group (one CO 2), and includes a C1-C6 alkylcarbol group. Acetyl group, propionyl group, ptylyl group, isoptylyl group, valeryl group, isovaleryl group, bivaloyl group and the like. [0032] The "lower alkylcarboxoxy group" is a group in which a lower alkylcarbo yl group is bonded to an oxygen atom, and specifically includes, for example, an acetoxy group, a propio- loxy group, a valeryloxy group, an isovaleryl group. Examples include a ruoxy group and a bivalyloxy group.

[0033] "Mono-lower alkyl force ruberamoyl group" is a hydrogen atom of force ruberamoyl group (one CONH)

2

One of these is a group substituted with a lower alkyl group. Specifically, for example, a methylcarbamoyl group, an ethylcarbamoyl group, an npropyl carbamoyl group, an isopropylcarbamoyl group, an n-butylcarbamoyl group, sec -A butylcarbamoyl group, a tert butylcarbamoyl group, etc. are mentioned.

[0034] The "di-lower alkyl force ruberamoyl group" means two hydrogens of force rubermoyl group (one CONH).

2

Specifically, each atom is a group substituted with a lower alkyl group. Specifically, for example, a dimethyl group, a rubamoyl group, a jetylcarbamoyl group, an ethylmethylcarbamoyl group, a di (n-propyl) rubamoyl group, a methyl ( (n-propyl) strong rubermoyl group, diisopropylcarbamoyl group and the like.

[0035] "Mono-lower alkyl strength ruberamoyloxy group" is a group in which a mono-lower alkylcarbamoyl group is bonded to an oxygen atom, and specifically includes, for example, methylcarbamoyloxy group, ethylcarbamoyloxy group, n Examples thereof include propyl group ruberamoyloxy group, isopropyl group ruberamoyloxy group, n-butylcarbamoyloxy group, sec butylcarbamoyloxy group, tert-butylcarbamoyloxy group and the like.

The “di-lower alkyl strength ruberamoyloxy group” is a group in which a di-lower alkylcarbamoyl group is bonded to an oxygen atom. Specifically, for example, a dimethylcarbamoyloxy group, a jetylcarbamoyloxy group Ethylmethylcarbamoyloxy group, di (n propyl) force ruberamoyloxy group, methyl (n propyl) force ruberamoyloxy group, diisopropyl force ruberamoyloxy group and the like.

[0037] "Lower alkylsulfonyl group" is a lower alkyl group bonded to a sulfonyl group (SO 2).

2

Specifically, for example, methylsulfol group, ethylsulfol group, n-propylsulfol group, isopropylsulfol group, n-butylsulfol group, sec-butylsulfol group, Examples thereof include a tert-butylsulfol group.

[0038] "Mono-lower alkylsulfamoyl group" is a hydrogen atom of a sulfamoyl group (one SO NH). One of the children is a group substituted with a lower alkyl group. Specifically, for example, monomethylsulfamoyl group, monoethylsulfamoyl group, mono (n-propyl) sulfamoyl group, monoisopropylsulfamoyl group, mono (N-Butyl) sulfamoyl group, mono (sec-butyl) sulfamoyl group, mono (tert-butyl) sulfamoyl group and the like can be mentioned.

[0039] "Di-lower alkylsulfamoyl group" refers to two waters of a sulfamoyl group (one SO NH).

twenty two

Each of the elementary atoms is a group substituted with a lower alkyl group. Specifically, for example, dimethylsulfamoyl group, jetylsulfamoyl group, di (n-propyl) sulfamoyl group, diisopropylsulfamoyl group, di (n— Examples thereof include a butyl) sulfamoyl group, a di (sec-butyl) sulfamoyl group, and a di (tert-butyl) sulfamoyl group.

[0040] The "pharmaceutically acceptable salt thereof" of the compound represented by the formula (I) includes a pharmaceutically acceptable ordinary salt, and includes an amino group and a tertiary of the compound of the formula (I). Examples include acid addition salts in amines and acid addition salts in nitrogen-containing heterocycles.

[0041] Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate, maleate, fumarate, tartrate, citrate and ascorbate. And organic acid salts such as trifluoroacetate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate.

[0042] Hereinafter, in order to more specifically disclose the derivative of the present invention, various symbols used in formula (I) will be described in detail with specific examples.

In the formula, Az represents an azetidyl group optionally having a substituent.

[0044] The substituent in Az is preferably a hydroxyl group, an oxo group, a C1-C4 alkyl group optionally substituted with a fluorine atom or a hydroxyl group, optionally substituted with a fluorine atom or a hydroxyl group, However, C3-C4 cycloalkyl groups, C1-C4 alkoxy groups, sulfonyl groups, etc. are exemplified, for example, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, Examples include a cyclopropyl group, a cyclobutyl group, a fluoromethyl group, a 2-fluoroethyl group, etc., and in particular, a C1-C4 alkyl group optionally substituted with a fluorine atom or a hydroxyl group, or optionally a fluorine atom or a hydroxyl group. Although substituted, a C3-C4 cycloalkyl group is recommended. Further, these substituents may have 1 to 3, preferably 1 to 2, with respect to Az. Unsubstituted Az is also recommended.

[0045] Note that Az can also contain azetidine N-oxide.

[0046] More preferably, Az is azetidine 1-yl group, azetidine 3-yl group, N-methylazetidine 3-yl group, N-ethylazetidine 3-yl group, N- (n-propyl) azetidine 3- Group, N-isopropylazetidine 3-yl group, N cyclopropylzetidine 3-yl group, N-cyclobutylazetidine-3-yl group, N- (2-fluoroethyl) azetidine 3- Group, azetidine-2-yl group, N-methylazetidine-2-yl group, N-ethylazetidine 2-yl group, N- (n-propyl) azetidine-2-yl group, N-isopropylase Examples thereof include tidin-2-yl group, N-cyclobutylazetidine-2-yl group and the like, more preferably N-ethylazetidine 3-yl group, N-isopropylazetidine 3-yl group, N-ethylazetidine 2-yl group. Group, N- (n-propyl) Azetidine 2-yl group, N-isopropylazetidine 2-yl group, etc. are recommended.

[0047] L represents a single bond or an optionally substituted C1-C2 alkylene group.

[0048] The substituent in the "optionally substituted, optionally C1-C2 alkylene group" is preferably, for example, a hydroxyl group, a fluorine atom, or optionally a fluorine atom. /, C1-C6 alkyl group, optionally substituted with a fluorine atom, C1-C6 alkyloxy group and the like are exemplified, and more preferably, optionally substituted with a fluorine atom! However, C1-C4 alkyl groups are recommended.

[0049] Specifically, as L,

Single bond,

(CH) —

2

-CH (CH)

Three

One (CH)-(CH)-,

twenty two

— (CH) CH (CH)

twenty three

One (CH) -CH (OCH) One,

twenty three

More preferably, a single bond, an unsubstituted methylene group, and optionally a C1-C4 Although it is substituted with an alkyl group, an ethylene group or the like is recommended.

[0050] Note that L may be bonded at any of the 1, 2 and 3 positions of the azetidyl group, but when L is a single bond, L is bonded at the 1-position (nitrogen atom) or 2-position of the azetidinyl group. In addition, in the case of an L-butylene group, L cannot be bonded at the 1-position (nitrogen atom) of the azetidinyl group! / ヽ. And when L is an ethylene group, it is not particularly limited. Therefore, the following O-L-Az bonding modes are recommended. (Here, the substituents in L and Az are omitted.)

[0051] [Chemical 2]

[0052] Ar may optionally have a substituent, and may be a phenyl group or an optionally substituted group, and may represent a pyridyl group.

[0053] As a substituent in the "optionally substituted phenyl group" or "optionally substituted pyridyl group" of Ar, preferably a halogen atom, C1-C6 Examples thereof include an alkyloxy group, a C1-C6 alkyl group which may be optionally substituted with a fluorine atom, and more preferably a fluorine atom and a chlorine atom. Further, these substituents may have 1 to 3, preferably 1 to 2, with respect to Ar.

[0054] Preferable as Ar is a phenyl group, a 3-fluorophenol group, a 4-fluorophenol group, a 3-chlorophenol group, a 4-cyclophenol group, or 3,4-difluoro. Examples include a phenol group, a 5-chloropyridine-2-yl group, a 5-trifluoromethylpyridine-2-yl group, and a 5-fluoropyridin-2-yl group. Particularly, a 4-fluorophenyl group, 4-clonal phenyl groups, 3,4-difluorophenyl groups, 5-chromic pyridine 2-yl groups, etc. are recommended.

As a matter of fact, among the compounds of the formula (I) provided by the present invention, the following are preferred.

[0056] · 1— [4— (Azetidine 1-ylmethoxy) phenol] —4— [(5 Yl) methoxy] pyridine 2 (1H) -one,

• 1 [4 (azetidine 3-ylmethoxy) phenol] -4 [(4 fluorobenzyl) oxy] pyridin 2 (1H) —one,

• 1— [4— (azetidine-3-ylmethoxy) phenol] —4— [((4) -benzyl) oxy] pyridin 2 (1H) —one,

• 1— [4— (azetidine—3-ylmethoxy) phenol] —4— [(3, 4 difluorobenzyl) oxy] pyridin 2 (1H) —one,

• 4— [(5-chloropyridine 2 yl) methoxy] 1— {4— [(1 cyclopropinoreazetidin-3 yl) methoxy] phenol} pyridine 2 (1H) —one,

• 4— [(5-Chronic pyridine-2-yl) methoxy] — 1— {4— [(1 Isopropylazetidin-1-3-yl) methoxy] phenyl} pyridine-1 2 (1H) — On,

• 4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Isopropylazetidine 1- 3 yl) methoxy] phenyl} pyridine 1 2 (1H) —one,

• 1 [4 (azetidine 3-yloxy) phenol] 4 [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

• 4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Methylazetidine 3 yl) oxy] phenol} pyridine 2 (1H) —one,

• 1— {4— [(1-Ethylazetidine 3 yl) oxy] phenol} 4— [(4 Fluorobenzyl) oxy] pyridine 2 (1H) —one,

• 1 {4 [(1-Cyclobutylazetidine 3 yl) oxy] phenol} -4 [(4 Fluorobenzyl) oxy] pyridine 1 2 (1H) —one,

• 4— [(4 Fluorobenzyl) oxy] 1— {4— [(1 Propylazetidine— 3 yl) oxy] phenol} pyridine—2 (1H) —one,

• 4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Isopropylazetidine 1- 3 yl) oxy] phenol} pyridin-2 (1H) —one,

• 1— [4— (azetidine-3-yloxy) phenol] 4— [(5-Cylidinepyridine-2-yl) methoxy] pyridine 2 (1H) —one,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— {4— [(1-Methylazetidine 1 3 Yl) oxy] phenol} pyridin-2 (1H) -one,

• 4— [(5-chloropyridine 2 yl) methoxy] 1— {4— [(1 ethinoreazetidine 3 yl) oxy] phenol} pyridine-2 (1H) —one,

• 4— [((5-chloropyridine) -2-yl) methoxy] — 1— {4— [(1 propylazetidine-3 yl) oxy] phenyl} pyridine-2- (1H) —one,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— {4 -— [(1 Isopropylazetidin-3 yl) oxy] phenol} Pyridine 1 2 (1H) —one ,

• 4— [((5 cyclopentyl pyridine) 2-yl) methoxy] 1— {4— [(1 cyclobutinoreazetidin-3 yl) oxy] phenol} pyridine 2 (1H) —one,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[1— (2 Fluoroethyl) azetidine 3 yl] oxy} phenol) pyridine 2 (1H) —one,

• 1— (4— {[(2S) — 2-azetidine 1-propyl) oxy}-))-4 [(4 fluorobenzyl) oxy] pyridin 2 (1H) —one,

• 1— (4— {[(2R) — 2-azetidine— 1-ylpropyl] oxy} phenol) 4— [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

• 1— (4— {[(2S) — 2-azetidine 1-propyl] oxy}-)) 4 [(5

—Black mouth pyridine 1-yl) methoxy] pyridine 1 2 (1H) —one,

• 1— (4— {[(2R) —2 azetidine— 1—ylpropyl] oxy} phenol) —4— [(5

—Black mouth pyridine 1-yl) methoxy] pyridine 1 2 (1H) —one,

• 1— {4— [(2S) azetidine-2-ylmethoxy] phenol} 4-— ((5-chloropyridine-2-yl) methoxy] pyridine-2- (1H) —one,

• 4 [(5 Chloropyridine 2 yl) methoxy] 1 4 {[(2S) 1 Methylazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) —one,

• 4 [(5 Chloropyridine 2yl) methoxy] 1 4 {[(2S) 1-Ethylazetidine-2-yl] methoxy} phenyl) pyridine 2 (1H) -one,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[(2S) — 1-Propylazetidine-2-yl] methoxy} phenol) pyridine 2 (1H) — On,

• 4 [(5 Chloropyridine 2 yl) methoxy] 1 4 {[(2S) 1 Isopropyl Azetidine 2—yl] methoxy} phenol) pyridin 2 (1H) —one,

• 4 [(5 Chloropyridine 2yl) methoxy] 1 4 {[(2S) 1-Cyclobutylazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) -one,

• 4 [(4 Fluorobenzyl) oxy] -1- (4 {[1- (2 Hydroxyethyl) azetidine— 3 yl] oxy} phenol) pyridin-2 (1H) —one,

• 4— [(4 Fluorobenzyl) oxy] 1— (4— {[1— (2 Hydroxy 1-methylethyl) azetidine 3 yl] oxy} phenol) pyridine 2 (1H) ON,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[1— (2 Hydroxyethyl) azetidine 3 yl] oxy} phenol) pyridine 2 (1H) ON,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[1— (2 Hydroxy-1-methylethyl) azetidine— 3-yl] oxy} phenol) pyridine— 2 (1H) —on,

• 4 [(4 Fluorobenzyl) oxy] 1 {4 [(1 Isopropyl 1-Oxido azetidine 3 yl) methoxy] Phenenole} Pyridine 2 (1H) ON,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— {4— [(1 Isopropyl-1-oxydazetidine-3 yl) methoxy] phenol} pyridine 2 (1H) — On,

• 4 [(4 Fluorobenzyl) oxy] 1 {4 [(1-Methyl-1 oxydazezidine-3 yl) oxy] phenol} pyridine 2 (1H) —one,

• 1 {4 [(1-ethylyl 1-oxydazetidine 3-yl) oxy] phenol} 4 — [(4 fluorobenzyl) oxy] pyridine 1 2 (1H) ON,

• 4— [(4 fluorobenzyl) oxy] 1— {4— [(1 oxide 1 propylazetidine— 3 yl) oxy] phenol} pyridine 2 (1H) —one,

• 4 [(4 Fluorobenzyl) oxy] 1 {4 [(1 Isopropyl 1-oxide azetidine 3 yl) oxy] phenol} Pyridine 2 (1H) —one,

• 1 {4 [(1-Cyclobutyl-1 Oxidazetidine 3 yl) oxy] fael}

— 4— [(4 Fluorobenzyl) oxy] pyridine 1 2 (1H) ON,

• 4— [((5-chloropyridine) -2-yl) methoxy] — 1— {4— [(1 Methyl 1-oxidezetidine 3-yl) oxy] phenol} pyridine 2 (1H) —one,

• 4— [((5-chloropyridine) -2-yl) methoxy] — 1— {4— [(1 ethyl 1-oxy Doorzetidine 3yl) oxy] phenol} pyridine 2 (1H) ON,

• 4— [(5-chloropyridine 2 yl) methoxy] 1— {4— [(1 oxide 1 propylazetidine 3 yl) oxy] phenol} pyridine 2 (1H) ON,

• 4— [((5-chloropyridine) -2-yl) methoxy] — 1— {4— [(1 Isopropyl-1-oxydazetidine-3-yl) oxy] phenol} pyridine 2 (1H) ON,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— {4— [(1-Cyclobutyl-1-hydroxyaldehyde-3 yl) oxy] phenol} pyridine 2 (1H) ON,

• 4 [(4 Fluorobenzyl) oxy] 1 4 {[(2S) — 2— (1 Oxidoazetidine— 1—yl) propyl] oxy} phenol) pyridine— 2 (1H) —one,

• 4 [(4 Fluorobenzyl) oxy] 1 4 {[(2R) — 2— (1 oxydazetidine— 1 —yl) propyl] oxy} phenol) pyridine— 2 (1H) —one,

• 4— [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[(2S) —2— (1-Oxido azetidine 1 yl) propyl] oxy} phenol) pyridine 2 (1H) —On,

• 4— [(5-Chromium pyridine 2-yl) methoxy] 1— (4— {[(2R) — 2— (1-oxydoazetidine 1-yl) propyl] oxy} phenol) pyridine 2 (1H) — ON, • 4— [(5 Chloropyridine—2-yl) methoxy] 1— (4— {[(2S)-1-Methyl— 1-Oxidoazetidine 2-yl] methoxy} phenol ) Pyridine 1 2 (1 H) ON,

• 4 [(5 Chloropyridine-2-yl) methoxy] 1- (4 {[((2S) 1-Ethyl- 1 Oxidozetidine 2-yl] methoxy} -phenyl) pyridine 1 2 (1 H) ON, • 4— [(5 Chromium Pyridine—2-yl) methoxy] 1— (4— {[(2S)-1 Oxide— 1 —Propylazetidine-2-yl] methoxy} phenol) pyridine 1 2 (1H) -one, • 4 [((5) -pyridine pyridine 2-yl) methoxy] 1 4 {[(2S) 1 isopropyl — 1-oxydazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) —one, • 4 [(5 chloropyridine 2 yl) methoxy] 1 1 (4 {[((2S) 1-cyclobutyl — 1-oxydazetidine 2 yl) methoxy} phenol) Pyridine 2 (1H) —one, • 1— {4— [(1 Ethyl 2 hydroxyazetidine 3 yl) oxy] phenol}-4 — [(4 Fluorobenzyl) oxy] pyridine 1 2 (1H) On ,

• 4 [(4 Fluorobenzyl) oxy] 1 {4 [(2 Hydroxy-1 isopropyl Azetidine 3 yl) oxy] phenol} pyridine 2 (1H) —one,

• 4— [(5-chloropyridine 2 yl) methoxy] 1— {4— [(1 ethyl 2 hydroxyzetidine 3 yl) oxy] phenyl} pyridine 2 (1H) ON,

• 4— [(5-Chromium pyridine-2-yl) methoxy] 1— {4— [(2 Hydroxy 1-isopropylazetidine-3-yl) oxy] phenol} Pyridine 1 2 (1H )-on,

• 1 {4 [(1-Acetylazetidine-3-yl) oxy] phenol} -4 [(5 pyridine-2-yl) methoxy] pyridine-2 (1H) -one,

• 1 {4 [(1-acetylylazetidin-3-yl) oxy] phenyl} -4 [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

• 1— {4— [(1—Acetylazetidine— 3-yl) methoxy] phenol} —4— [(5 Chloropyridine-2-yl) methoxy] pyridine-2 (1H) —On,

• 1— {4 — [(1-acetylzetidine 3-yl) methoxy] phenol} 4 -— [(4 fluorobenzyl) oxy] pyridin 2 (1H) —one, and

• 1 1 (4— {[(2S) — 1-acetylylazetidine 2 yl] methoxy} file) -4 1 [(5 2 yl pyridine 1 2-yl) methoxy] -pyridine 1 2 (1H) —On.

Above all,

1— {4— [(1 ethylazetidine 3 yl) oxy] phenol} 4— [(4 Fluorobenzyl) oxy] pyridine 2 (1H) —one,

4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Isopropylazetidine-1-3-yl) oxy] phenol} pyridin-2 (1H) —one,

1— [4— (azetidine 1-yloxy) phenol] 4— [(5-Cloylpyridine 1- 2-yl) methoxy] pyridine 2 (1H) —one,

4— [(5-chloropyridine 2 yl) methoxy] 1— {4— [(1 ethenoreazetidine 3 yl) oxy] phenol} pyridine-2 (1H) —one,

4— [(5 Chloropyridine 1-yl) methoxy] 1— {4— [(1 Propylazetidine 1

3yl) oxy] phenyl} pyridin-2 (1H) -one,

4— [(5 Chlorocyclic pyridine-2-yl) methoxy] 1— {4 -— [(1 Isopropylazetidin-1 yl) oxy] phenol} Pyridine 1 2 (1H) —one, l-(4- {[((2S) 2 azetidine 1-propyl) oxy} phenyl) -4 [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

1— (4— {[(2R) — 2-azetidine— 1-ylpropyl] oxy} phenol) 4— [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

4— [(5 Chloropyridine—2-yl) methoxy] 1— (4— {[(2S) -1-Methylazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) —one,

4 [(5 Chloropyridine 2yl) methoxy] 1 (4 {[(2S) 1 Ethylazetidine 2-yl] methoxy} phenyl) pyridine 2 (1H) -one, and

4— [(5 Chloropyridine 1- 2-yl) methoxy] 1- (4— {[(2S)-1-Isopropylzetidine-2-yl] methoxy} phenol) pyridine-2 (1H) —On, etc. is recommended.

4— [(5-chloropyridine-2-yl) methoxy] 1— {4— [(1 isopropylazetidin-3 yl) oxy] phenol} pyridine-2 (1H) ON, and

4 [(5 Chloropyridine 2yl) methoxy] 1 4 {[(2S) 1 Ethylazetidine-2-yl] methoxy} phenyl) pyridin-2 (1H) -one is recommended.

[0058] Method for producing compound represented by formula (I)

The compound represented by the formula (I) can be prepared, for example, by the following production method or the method shown in Examples. However, the production method of the compound of the present invention is not limited to these examples.

[0059] Manufacturing Method 1 The compound represented by the formula (I) can be produced by reacting the compound represented by the formula (Π) with the compound represented by the formula (ΠΙ).

[0060] [Chemical 3] Reaction scheme 1

[Wherein J represents a hydroxyl group or a leaving group, and Ar, L, and Az have the same meanings as described above. ]

[0061] When J is a leaving group, the reaction between the compound represented by the formula (ΠΙ) and the compound represented by the formula (Π) is usually performed by condensing both in an organic solvent in the presence of a base. This can be done.

[0062] Examples of the leaving group in J include a bromine atom, a chlorine atom, a benzenesulfonyloxy group, a p-toluenesulfo-oxy group, and a methanesulfo-oxy group.

[0063] Examples of the organic solvent include halogenated carbons such as methylene chloride, chloroform, and dichloroethane; aliphatic hydrocarbons such as n heptane and n-hexane; aromatic hydrocarbons such as benzene, toluene, and xylene. Ethers such as jetyl ether, tetrahydrofuran (hereinafter referred to as “THF”), 1,4 dioxane (hereinafter referred to as “dioxane”), ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; Examples include acetonitrile, N, N-dimethylformamide (hereinafter referred to as “DMF”), dimethyl sulfoxide (hereinafter referred to as “DMS Oj t”), and mixed solvents thereof.

[0064] Examples of the base include organic amines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine; sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, carbonate Inorganic amines such as cesium, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are exemplified, and potassium carbonate, cesium carbonate and the like are recommended.

[0065] The amount of the compound represented by the formula (ΠΙ) to be used is, for example, 0.9 mol to 2.0 mol, preferably 1.1 mol, per 1 mol of the compound represented by the formula (Π). To 1.5 moles is recommended. [0066] The amount of the base used is, for example, 1 mol to 10 mol, preferably 2 mol to 3 mol per mol of the compound represented by the formula (Π).

[0067] The reaction temperature is, for example, 20 ° C to 150 ° C, preferably 60 ° C to 100 ° C is recommended, and the reaction is usually completed in 1 to 3 hours.

[0068] In addition, when J is a hydroxyl group, the reaction between the compound represented by the formula (ΠΙ) and the compound represented by the formula (Π) can be usually performed under the conditions of Mitsunobu reaction.

[0069] That is, in a reaction solvent, an azo compound such as dialkyl azodicarboxylate or 1,1 '(azo dicarbol) diamide and an organic phosphorus compound such as triaryl phosphine or trialkyl phosphine. In the presence, the compound represented by the formula (I) is obtained by condensing the compound represented by the formula (ΠΙ) with the compound represented by the formula (Π).

[0070] Examples of the azo compound include dimethylazodicarboxylate, jetylazodicarboxylate, diisopropylazodicarboxylate, 1,1 '(azodicarbol) dipiperidide, and the like, and triarylphosphine Examples of the trialkylphosphine include triphenylphosphine and tributylphosphine. Examples of the trialkylphosphine include triethylphosphine and tributyphosphine. Of these, the combination of diisopropyl azodicarboxylate and triphenylphosphine, or the combination of 1,1,-(azodicarbol) dipiperidide and tributylphosphine is recommended.

[0071] The amount of the compound represented by the formula (III) is 1 to 10 mol, preferably 1 to 1.5 mol per 1 mol of the compound represented by the formula (Π). Recommended.

[0072] The use amount of the azo compound and the organophosphorus compound is exemplified by 1 mol to 3 mol of the azo compound per 1 mol of the compound represented by the formula (Π), preferably 1 1 mol to 1.5 mol is recommended, and 1 mol to 3 mol of the organic phosphorus compound is exemplified with respect to 1 mol of the compound represented by the formula (Π), preferably 1 mol to 1.5 mol. Recommended.

[0073] Examples of the reaction solvent include halogenated carbons such as methylene chloride, chloroform, dichloroethane, and carbon tetrachloride; aliphatic hydrocarbons such as n heptane and n-hexane; benzene, toluene, and xylene. Aromatic hydrocarbons such as: ethers such as jetyl ether, THF, dioxane, and ethylene glycol dimethyl ether; esters such as methyl acetate and ethyl acetate; acetonitrile, N-methylpyrrolidone (hereinafter referred to as “NMP”) ), DMF, DMSO Or a mixed solvent thereof.

[0074] The reaction temperature is, for example, 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C is recommended, and the reaction is usually completed in 2 hours to 24 hours.

[0075] The compound represented by the formula (Π) can be produced, for example, by the method described in International Publication WO2005Z085200.

[0076] The compound represented by the formula (III) can be prepared by the method described in the Examples, as well as Chemical and Pharmaceutical Bulletin, Vol. 22, 1490 (1974), Journal of Hetero cyclic Chemistry, Vol. 24, 255. (1987) and JP-A-2000-143622, etc., or a method analogous thereto.

[0077] In the above reaction, when there is an amino group, a hydroxyl group, or the like in the reactant, there is an amino group, a hydroxyl group, etc. After protecting with a group, each reaction of the above production method can be carried out, and the protecting group can be removed after the reaction.

[0078] Introduction of Protecting Group The method of removing Z varies depending on the type of protecting group and the stability of the compound used, but the protection groups in organic synthesis, TW ureen, 2 / ¾χ, John Wiley & Sons, 1991).

[0079] The protecting group for the amino group is not particularly limited as long as it has the function, and examples thereof include a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, and a trityl group. Aralkyl group; lower alkanol group such as acetyl group, propionyl group and bivaloyl group; benzoyl group; aralkyl alkanol group such as ferroacetyl group; methoxy carbo yl group, ethoxy carbo yl group, tert-butoxy carbo Lower alkoxycarbonyl group such as benzyl group; benzyloxycarbonyl group, aralkyloxycarbol group such as p--trobenzyloxycarbonyl group; trimethylsilyl group, tert-butyldimethyl Lower alkylsilyl group such as silyl group; tetrahydrobiranyl group; trimethylsilylethoxymethyl group; methylsulfol group, ethylsulfol group Lower alkylsulfonyl of - Le group; benzenesulfonyl - group, toluenesulfonyl - Arirusuruho such Le group - Le group, and the like et be. [0080] The protecting group for the hydroxyl group is not particularly limited as long as it has the function thereof, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group; a trimethylsilyl group, a tert-butyldimethylsilyl group Lower alkylsilyl group such as methoxymethyl group, 2-alkoxymethyl group such as 2-methoxyethoxymethyl group, etc .; tetrahydrovinyl group; trimethylsilylethoxymethyl group; benzyl group, p-fluorobenzoyl group, p- Examples thereof include aralkyl groups such as methoxybenzyl group, 2,3-dimethoxybenzyl group and trityl group; and acyl groups such as formyl group and acetyl group.

[0081] Manufacturing method 2

The compound represented by the formula (1-1) can be produced by reacting the compound represented by the formula (IV) with the compound represented by the formula (V).

[0082] [Chemical 4] Reaction scheme 2

[Wherein, X represents a leaving group, formyl group or oxo group, Az ^p represents an azetidyl group which may be protected, Azl represents an azetidyl group, and R optionally represents fluorine. A lower alkyl group that may be substituted with an atom or a hydroxyl group, or a lower cycloalkyl group that may optionally be substituted with a fluorine atom or a hydroxyl group is shown, and Ar and L are as defined above. ]

[0083] In the case where Az ^{P of the} compound represented by the formula (IV) has a protecting group, after deprotection by the method described in the above-mentioned Protective Groups in Organic Synthesis, By carrying out the reaction, the formula (1-1) can be produced. [0084] At this time, the reaction between the compound represented by the formula (V) in which X is a leaving group and the deprotected compound represented by the formula (IV) can be performed according to Production Method 1. it can.

[0085] Also, in the formula (V)! / When X is a formyl group or an oxo group, after deprotecting the compound represented by the formula (IV), in an organic solvent in the presence of a reducing agent, Condensation with compound of formula (V)

(Reductive amination) to obtain a compound represented by the formula (I 1).

[0086] The amount of the compound represented by the formula (IV) and the compound represented by the formula (V) is usually used by using equimolar amounts of either or a small excess of either one.

[0087] Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc biscianoborohydride, nickel biscianoborohydride and the like.

[0088] The amount of the reducing agent to be used is, for example, 1 mol to excess mol per mol of the compound represented by the formula (IV), and preferably 1 mol to 5 mol is recommended.

[0089] Examples of organic solvents include alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, THF, and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloromethane; benzene, toluene, Aromatic hydrocarbons such as black benzene and xylene; solvents such as DMF and acetonitrile, or mixed solvents thereof.

[0090] The reaction temperature is usually 20 ° C to 100 ° C, preferably 0 ° C to room temperature, and the reaction time is usually 5 minutes to 7 days, preferably 1 Time 6 to 6 hours.

[0091] The compound represented by the formula (V) includes alkyl halides such as methyl iodide, iodide til, and propyl bromide; lower alkyl aldehydes such as formaldehyde and acetoaldehyde; acetone, cyclobutanone, and the like. And lower alkyl carbo yl and the like.

[0092] Manufacturing method 3

A compound represented by the formula (I2) can be produced by reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII).

[0093] [Chemical 5] Reaction) ⁺

,

(VII)

厂 '■ IR

(1-2)

[Wherein J and J are the same or different, and optionally protected by hydroxyl group or

1 2

Represents a leaving group, and Ar, L and R are as defined above. ]

[0094] The compound represented by the formula (VII) can be produced by reacting the compound represented by the formula (Π) and the compound represented by the formula (VI) according to the production method 1. it can.

[0095] When J is a leaving group, a compound represented by the formula (VII) and a compound represented by the formula (VIII)

2

This reaction can be carried out according to production method 1.

[0096] On the other hand, when J is a hydroxyl group having a protecting group, the protecting group is removed, and p

2

After conversion to a leaving group such as an enesulfonyloxy group, a compound represented by the formula (I-2) can be obtained by performing a reaction according to Production Method 1.

[0097] Examples of the compound represented by the formula (VI) include 1, 2 dibromoethane, 2 bromoethanol, (2R) -2- (tetrahydro-1-2H-pyran-2-yloxy) propyl methanesulfonate, (2S)- Examples include 2- (tetrahydro-1,2H-pyran-1,2-yloxy) propyl methanesulfonate and the like.

[0098] Examples of the compound represented by the formula (VIII) include azetidine, 3-hydroxyazetidine, 2-methylazetidine, 3-methylazetidine, and the like.

[0099] The compound represented by the formula (I) obtained by force, the compound represented by the formula (I 1) or the compound represented by the formula (I 2) can be obtained by conventional separation means, for example, solvent extraction. It can be easily isolated and purified by recrystallization, column chromatography, preparative thin layer chromatography or the like. [0100] These compounds can be converted into pharmaceutically acceptable salts by a conventional method, and vice versa.

In addition, conversion to a salt-free compound can also be performed according to a conventional method.

[0101] The action of the compound of the present invention as an MCH receptor antagonist is proved, for example, by the following pharmacological test examples.

[0102] Physical Test Example 1: MCH binding defects.

The cDNA sequence encoding human MCH-1R [FEBS Letters, Vol. 398, 253 (1996); Biochimica et Biophisica Acta, Vol. 1401, 216 (1998)] was cloned into the plasmid vector pEFZmycZcyto (Invitrogen). did. Using the resulting expression vector using lipofectamine plus reagent (manufactured by Life Technology Co., Ltd.), host cells

MCH 1R-expressing cells were obtained by transfection with CHO-K1 (American Type · Collection · Collection).

[0103] Cell force expressing this MCH-1R A membrane preparation prepared with test compound and 50 pM

[ ¹²⁵ I] MCH (manufactured by NEN) and Atssey buffer (50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediamine tetraacetic acid, 0.01% bacitracin and 0.2% ushi serum albumin, pH 7.4 ) At 25 ° C. for 1 hour, and then filtered through a glass filter GF / C (manufactured by Whatman). The glass filter was washed with 50 mM Tris buffer, pH 7.4 containing 10 mM magnesium chloride, 2 mM ethylenediaminetetraacetic acid and 0.04% Tween-20, and the radioactivity on the glass filter was determined. Nonspecific binding was measured in the presence of 1 μM human MCH, and the 50% inhibitory concentration (IC value) of the test compound for specific [ ¹² ¾ MCH binding was determined. The results are shown in Table 1.

50

[0104] [Table 1]

Experiment f row 2: (Eating test of mice in a boat) C Feeding high fat diet to male C57BLZ6 mice (10-12 weeks old) to form dietary obesity I let you. Various amounts of the compound of Example 18 were suspended in 0.5% aqueous methylcellulose solution and orally administered 1-2 hours before the start of the dark period. Subsequently, mice were fed with a high fat diet, and spontaneous food intake was measured up to 24 hours after administration.

[0106] FIG. 1 is a graph showing spontaneous food intake of mice up to 24 hours after oral administration of 30 mgZkg of the compound of the present invention to mice with dietary obesity. That is, 1) when the compound of Example 18 is not administered, and 2) when 30 mg Zkg of the compound of Example 18 is administered, the spontaneous food intake (g) of mice for 24 hours is shown.

[0107] The compound of the present invention significantly suppressed the spontaneous food intake of mice that had formed dietary obesity in a dose-dependent manner. In addition, the amount of food consumed when only a 0.5% aqueous solution of methylcellulose was administered instead of the compound of the present invention was used as a control.

Accordingly, the present invention relates to metabolic diseases such as obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction. Circulatory system diseases such as atherosclerosis, hypertension, kidney disease, electrolyte abnormalities, such as bulimia, emotional disorder, depression, anxiety, hemorrhoids, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, Central and peripheral nervous system diseases such as memory disorders, sleep disorders, cognitive disorders, motor disorders, sensory abnormalities, olfactory disorders, morphine tolerance, narcotic addiction, alcoholism, such as infertility, premature birth, sexual dysfunction It can be used for preventive or treatment of systemic diseases, gastrointestinal diseases, respiratory diseases, cancer or skin pigmentation.

[0109] Include ^^ in expression m

The compound of the present invention can be administered orally or parenterally, and by formulating it into a form suitable for its administration, obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis , Metabolic diseases such as cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities, such as bulimia, affective disorders, Depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormality, olfactory disturbance, morphine tolerance, drug dependence, alcohol Serve as a preventive or therapeutic agent for central and peripheral nervous system diseases such as addiction, for example, reproductive system diseases such as infertility, premature birth, sexual dysfunction, and other diseases, gastrointestinal diseases, respiratory diseases, cancer be able to. [0110] In clinical use of the compound of the present invention, it is also possible to add a pharmaceutically acceptable carrier according to the administration form and administer it after various preparations. As the carrier at that time, various conventionally known additives in the pharmaceutical field can be used. For example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn Starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, cured Castor oil, polybulurpyrrolidone, magnesium stearate, light anhydrous key acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol Le,

[0111] Examples of dosage forms formulated as a mixture of these carriers and the compound of the present invention include solid preparations such as tablets, capsules, granules, powders or suppositories; or, for example, syrups and elixirs. Alternatively, liquid preparations such as injections can be mentioned, and these can be prepared according to conventionally known methods in the field of preparations. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, it may be dissolved or suspended in physiological saline or glucose solution as necessary, and a buffer or preservative may be added.

[0112] These preparations can contain the compound of the present invention in a proportion of 1.0 to: LOO wt%, preferably 1.0 to 60 wt% of the entire pharmaceutical composition, The above-acceptable carrier can be contained in an amount of 0 to 99.0% by weight, preferably 40 to 99.0% by weight. These preparations may contain other therapeutically effective compounds such as a therapeutic agent for diabetes, a therapeutic agent for hypertension, a therapeutic agent for arteriosclerosis and the like.

[0113] When the compound of the present invention is used for the prophylaxis or treatment of the diseases as described above, the dosage and frequency of administration are the patient's sex, age, weight, degree of symptom, and type of desired therapeutic effect. The dose is usually from 0.001 to 50 mg / kg body weight per day, and can be administered in single or multiple doses. The dosage is preferably about 0.01 to about 25 mg Zkg per day, about 0.05 to about 25 per day. 1 Omg / kg is more preferred!

[0114] Combination therapy using a compound represented by formula ω

The compound of the present invention is a drug effective for hypertension, hypertension related to obesity, hypertension related diseases, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity related diseases, etc. (hereinafter referred to as “combination drug”). ) Can be used in combination. Such drugs can be administered simultaneously, separately or sequentially in the prevention or treatment of the disease. When the compound of the present invention is used at the same time as one or more concomitant drugs, it can be a pharmaceutical composition in a single dosage form. However, in combination therapy, the composition containing the compound of the present invention and the concomitant drug may be administered to the administration subject in different packages simultaneously, separately or sequentially. They may be administered with a time lag.

[0115] The dose of the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease, combination, etc., in accordance with the clinically used dose. The administration form of the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include: 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate administration of the compound of the present invention and the concomitant drug. Simultaneous administration of two preparations obtained by formulation in the same administration route, 3) Time difference in the same administration route of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug 4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, 5) Compound of the present invention and the concomitant drug Administration of two different preparations obtained by separate formulation in different routes of administration (e.g. compound of the invention; administration in concomitant order of drugs or in reverse order) Administration). The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.

Examples of the concomitant drug used in the present invention include “diabetes therapeutic drug”, “hyperlipidemic therapeutic drug”, “hypertension therapeutic drug”, “anti-obesity drug” and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.

[0117] Specific drugs include simvastatin; mepastatin (mevastatin) Ezetimibe; atorvastatin; sitagliptin; metformin; sibutramine; onorlistat, orlist at; knexa; topiramate; phen Theremin (phentermine); oral sartan; combination of losartan and hydrothiazia thiazide; or rimonabant, N— [3— (4 chlorophenol) 2 (S) —felue 1 ( S) Methyl propyl] — 2— (4 trifluoromethyl— 2 pyrimidyloxy) —2—methylpropanamide, N— [(IS, 2S) —3— (4—black mouth) 2— (3— Cyanophylol) 1 1-Methylpropyl] 2 Methyl 2— {[5 (Trifluoromethyl) pyridine— 2yl] oxy} propanamide, N— [3— (4 Closures) 2— (5 black mouth 3 pyridyl) 1-methylpropi ] — 2— (5-Trifluoromethyl-1,2-pyridyloxy) 2-methylpropanamide, 3-— {1 [Bis (4-cyclohexane) methyl] azetidine 3 Iridene} -3 (3 , 5 Difluorophenol) -2, 2 Dimethylpropane-tolyl, 1 {1 [1 (4 Chlorophthalate) pentyl] azetidine-3-yl} -1 (3,5 Difluorophenol) 2 Methyl Propane 2 ol, 3 ((S) (4-chlorophenol) {3— [(1S) —1 (3, 5 difluorophenol) -2 hydroxy-2 methylpropyl] azetidine-1-yl} methyl ) Benzo-tolyl, 3— ((S)-(4 Chlorophenol) {3— [(1S) 1 (3,5 Difluorophenol) 2 Fluoro-2-methylpropyl] azetidin— 1-yl} methyl ) Benzo-tolyl, 3— ((4 black mouth)) {3— [1— (3, 5 Difluorophenyl) -2,2-dimethylpropyl] azetidine 1 Methyl} benzo) tolyl, 3 -— ((1S) — 1 {1 [(S) — (3 cyanophyl) (4 cyanophyl) methyl] azetidine 3-yl} 2 fluoro-2-methylpropyl) 5 Fluorobenzene-tolyl, 3— [(S)-(4 Chlorophenol) (3— {(1S) —2 Fluoro 1— [3— Fluoro 5— (4Η—1, 2, 4 Triazol 4 2) Methylpropyl} azetidine- 1-yl) methyl] benzo-tolyl, 5— ((4-Chanophenol) {3— [1 (3, 5 difluorophenol) -2 fluoro- 2-methylpropyl] azetidine 1-yl} methyl) thiophene 3 carbo-tolyl, 3— [(S) — (4-chlorophenol) (3— {(1S) — 2 fluoro 1— [3 fluoro 5— (5 — oxo 4,5 dihydro-1,3,4 oxadiazol 2 yl) file] -2 methylpropyl} azetidine 1yl) methyl] benzonitrile, 3— [(S) — (4-chlorophenyl) (3— {(lS) —2—fluoro-1 [3 fluoro-5— (1, 3, 4 oxazodiazole 2 yl) Phenyl] -2 Methylpropyl} azetidine-1-yl) methyl] benzo-tolyl, 3— [(S) — (3— {(IS) — 1— [3— (5 amino— 1, 3, 4— Oxadiazole—2-yl) -5 fluorophenyl] 2 fluoro-2-methylpropyl} azetidine 1-yl) (4-chlorophenyl) methyl] benzonitrile, 3- [(S) — (4-Cyanofynyl) ( 3— {(1S) — 2 Fluoro 1 [3 Fluoro 5— (5 oxo 4,5 dihydro-1,3,4 oxadiazole—2-yl) phenyl] —2-methylpropyl} azetidine—1-yl) Methyl] benzo-tolyl, 3— [(S) — (3— {(1S) — 1 [3— (5 amino-1, 3, 4 oxadiazol 2 yl) 5 fluorofe- ] 2 Fluoro-2-methylpropyl} azetidine— 1-yl) (4 cyanophyl) methyl] benzo-tolyl, 3-— [(S)-(4 cyanophyl) (3— {(13) —2-fluoro 1 [3-Fluoro-5- (1, 3, 4 oxadiazol 2-yl) phenol] 2-Methylpropyl} azetidine 1-yl) methyl] benzo-tolyl, 3— [(S) — (4 Chlorophenyl -L) (3— {(1S) —2—Fluoro — 1— [3 Fluoro 5— (1, 2, 4-Oxadiazole— 3-yl) phenol] — 2— Methylpropyl} azetidine 1 yl ) Methyl] benzo-tolyl, 3— [(1S) —1 (1 {(S) one (four cyanophages) [3— (1, 2, 4, one oxadiazo one ruyl three fils)] —Methyl} azetidine-3-yl) —2 Fluoro-2-methyl] —5 Fluorobenzonitryl, 5 -— (3— {1 [1 (Diphenylmethyl) azetidine 3-yl] 2 Fluoro 2 Rupuropiru} over 5 Furuorofe - Le) 1H-tetrazole, 5- (3- {1

[1- (Diphenylmethyl) azetidine 3-yl] 2 Fluoro-2 methylpropyl} -5 fluorophenyl) 1-Methyl-1H-tetrazole, 5-— (3— {1— [1— (Diphenylmethyl) azetidine 3—yl] 2 fluoro-2-methylpropyl} 5 —fluorophenyl) 2-methyl 2H-tetrazole, 3— [(4-chlorophage) (3 {2 fluoro-1 [3 fluoro-5- (2— Methyl-2H-tetrazole-5-yl) phenol] -2 Methylpropyl} azetidine-1-yl) methyl] benzo-tolyl, 3 [(4-chlorophenol) (3- {2-Fluoro 1 [3-Fluoro 5 — (1-Methyl-1H-tetrazole-5 file) 2] Methylpropyl} azetidine 1-yl ) Methyl] benzo-tolyl, 3— [(4-Cyanophyl) (3— {2 Fluoro 1— [3 Fluoro 5— (1-Methyl-1H-tetrazol-5 yl) phenol] 2 Methylpropyl} azetidine — 1—yl) methyl] benzo-tolyl, 3— [(4-cyanophyl) (3— {2 -fluor 1— [3 fluoro 5— (2 methyl 2H tetrazole 5 yl) file] — 2 Methylpropyl} azetidine— 1-yl) methyl] benzonitrile, 5-{3- [(S) {3 [(IS) —1 (3 Bromo-5 fluorophenyl) -2 fluoro-2 methylpropyl] azetidine 1 1} (4 black-mouthed) methyl] phenyl} 1, 3, 4 oxadiazoluo 2 (3H) —one, 3— [(13) —1— (1 {(3) — (4− (Chlorophenol) [3— (5-oxo-4, 5 dihydro-1, 3, 4, 4-oxadiazol 2-yl) phenol] methyl} azetidine 3 yl) 2 fluor 2 me Rupropyl] 5 Fluoro Benzo-Tolyl, 3— [(1S) —1 (1 {(S) — (4 Sheanophenol) [3 — (5—Oxo 4, 5 Dihydro 1, 3, 4— Oxazazol 2—yl) phenyl] methyl} azetidine 3 yl) 2 fluoro-2-methylpropyl] 5 fluobenzobenzotolyl, 3— [(IS) — 1— (1— {(S ) — (4 Cyanol) [3— (1, 3, 4—Oxadiazol 2 yl) phenol] Methyl} azetidine— 3 yl) 2 Fluoro —2—Methylpropyl] — 5 Fluoroben Zo-tolyl, 3— [(1S) — 1— (1— {(S) — (4 chlorophenyl) [3— (1, 3, 4—oxaziazol 2-yl) phenol] methyl } Azetidine 3 yl) 2 Fluoro-2-methylpropyl] 5 Fluorobenzobenzoyl, 3 -— ((1S) — 1 {1 [(S) — [3— (5 Amino-1, 3, 4-oxo Diazole-2) Fuel] (4—Black mouth phenyl) ] Azetidine 3 yl} 2 Fluoro 2-methylpropyl) -5 fluorobenzoic tolyl, 3— ((IS) — 1— {1— [(S) — [3— (5 amino-1, 3, 4—Oxadiazol 1—2) Fuel] (4 Cyanol) Methyl] azetidine—3 Fil} 2 Fluoro 2 Methylpropyl) 5 Fluorobenzobenzonitrile, 3— [(1S) —1 (1 {(S) — (4 Cyanofynyl) [3— (1, 2, 4, 4 oxadiazol 3 yl) phenol] methyl} azetidine 3 yl) 2 Fluoro 2-methylpropyl] — 5 Fluoro Benzo-Tolyl, 3— [(IS) — 1— (1— {(S) One (4 Black Mouth) [3— (1, 2, 4 ) Fuel] methyl} azetidine 3 yl) 2 Fluoro-2-methylpropyl] 5 Nzo-tolyl, 5— [3— ((S)-(4 Chlorophenol) {3— [(1S) — 1— (3,5 Difluorophenol) 2-Fluoro-2-methylpropyl] azetidine 1 -Methyl} methyl) phenol] -1,3,4-oxadiazol-2 (311) -one, 5- [3 -— ((3)-(4-chlorophenol) {3— [(lS) —l— (3,5 difluorophenyl) 2 fluoro-2-methylpropyl] azetidine—1-yl} methyl) phenyl] — 1, 3, 4-oxoxadiazole— 2 (3H) ON, and 4 {(S) — {3— [(1S) — 1 (3,5 difluorophenyl) 2-fluoro-2-methylpropyl] azetidine-1-yl} [3— (5 oxo-4,5 dihydro 1, 3, 4-Oxadiazole- 2-yl) phenol] methyl} benzo-tolyl group power selected CB1 Antagost Z Inverseagost or pharmaceutically acceptable salt or prodrug thereof Etc. I can get lost.

[0118] The above combination drug can be obtained by using one or more of the compound of the present invention and the above combination drug in combination. In addition, the above combination drug is useful for prevention or treatment of metabolic diseases by combining with one or more drugs selected from the group power consisting of antidiabetic drugs and hyperlipidemia drugs. In particular, combinations containing antihypertensive drugs and antihypertensive drugs are useful for the prevention or treatment of metabolic diseases with a synergistic effect by adding antidiabetic drugs and Z or hyperlipidemia drugs.

[0119] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the examples. The various reagents used in the examples were commercially available unless otherwise specified. As column silica gel, WakogelTM C-200 (Wako Pure Chemical Industries, Ltd.), WakogelTM C-300 (Wako Pure Chemical Industries, Ltd.), KP-Sil series or KP-NH series (Biotage) is used. As a preparative thin layer chromatography, Kieselgel 60F254 (Merck) was used. 1H-NMRi manufactured by EOL, AL-400-2 (400 MHz) was used, and measurement was performed using tetramethylsilane as a standard substance. The mass spectrum was measured by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) using Waters micromassZQ.

Example

[0120] Example 1

1— [4— (azetidine 1-ylmethoxy) phenol] 4— [(5- Lu) methoxy] pyridine 2 (1H) -one

[Chemical 6]

(1) Preparation of 4- (benzyloxy) 1- [4- (tetrahydro-2H pyran-1-yloxy) phenyl] pyridin-2 (1H) -one

4 (Benzyloxy) pyridine 2 (1H) one (170 g, 0.84 mol), 2- (4-dodophenoxy) tetrahydro 2H pyran (360 g, 1.18 mol), cuprous iodide (56.3 g, 0.30 mol), potassium carbonate ( 245 g, 1.77 mol) and N, N-dimethylformamide (30 OOmL) were stirred at 150 ° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and poured into water (12 L), and the insoluble material obtained was collected by filtration. To the resulting residue was added black mouth form (3 L) and stirred vigorously at room temperature for 20 minutes. The insoluble material was filtered off, and the filtrate was washed successively with 10% aqueous ammonia and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (218 g, 68%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.55— 1.75 (3Η, m), 1.82— 1.90 (2

Three

H, m), 1.95— 2.05 (1H, m), 3.56— 3.64 (1H, m), 3.85— 3.93 (1H, m), 5.03 (2H, s), 5.45 (1H, t, J = 3.2Hz) , 6.01 (1H, d, J = 3.2Hz), 6.05 (1H, dd, J = 8.8, 3.2H), 7.12 (2H, d, J = 8.8Hz), 7.20 (1H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8Hz), 7.35—7.43 (5H, m).

(2) 4-Hydroxy 1— [4 (Tetrahydro 2H pyran 2 yloxy) phenol] Preparation of pyridin 2 (1H) —one

4- (Benzyloxy) 1- [4- (Tetrahydro-2H-pyran-2-yloxy) phenol] pyridin-2- (1H) -one (129 g, 0.34 mol) in THF (1000 ml) -methanol (1200 ml) 10% Palladium-activated carbon (wet, 72. Og) was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere (1 atm). The reaction solution was filtered and washed well with a mixed solvent of black mouth form (1500 ml) -methanol (500 ml), and then the filtrate was concentrated under reduced pressure. To the resulting residue Ethyl acetate was added, and the solid was collected by filtration and dried under reduced pressure to give the title compound (136 g, 98%) as a colorless solid.

'HNMR (300MHz, DMSO-d, 6ppm): 1.46— 1.95 (6Η, m), 3.50— 3.

6

60 (1H, m), 3.71-3.80 (1H, m), 5.50 (1H, s), 5.61 (1H, d, J = 2.4Hz), 5.91 (1H, dd, J = 8.4, 2.4Hz), 7.08 (2H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz), 7.45 (1H, d, J = 8.4Hz).

(3) Preparation of 2-bromo-5-black pyridine

30% odorous hydrogen hydrogen oxalic acid solution (1500 ml) and water (100 ml) were poured into 2,5-dichlorodipyridine (300 g, 2.03 mol) and stirred at 110 ° C. for 4 days. The reaction mixture was cooled to room temperature, diluted with hexane (1000 ml), and the precipitate was collected by filtration. The obtained solid was suspended in water (5000 ml), sodium carbonate was gradually added to neutralize the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (366 g, 94%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 7.41 (1Η, d, J = 8.0Hz), 7.51 (1H, d

Three

d, J = 8.0, 2.4Hz), 8.33 (1H, d, J = 2.4Hz).

(4) Production of ethyl 5-chloropyridine-2-carboxylate

2-Bromo-5-chloropyridine (253 g, 1.32 mol), palladium acetate (14.8 g, 65.9 mmol), 1,1, monobis (diphenylphosphino) pheucene (73.0 g, 132 mmol), triethylamine (385 ml, 2.76 mol) DMF (1000 ml) -ethanol (1000 ml) mixed solution was stirred overnight at 50 ° C. in a carbon monoxide atmosphere. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the insoluble material was filtered off. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (208 g, 85%) as a yellow solid.

'HNMR (300MHz, CDC1, 6ppm): 1.45 (3Η, t, J = 7.2Hz), 4.47 (2H, q

Three

, J = 7.2Hz), 7.83 (1H, dd, J = 7.8, 2.4Hz), 8.10 (1H, d, J = 7.8Hz), 8.70 (1H, d, J = 2.4Hz).

(5) Manufacture of (5-chloro-pyridine-2-yl) methanol Ethyl 5 Chloropyridine pyridine 2-carboxylate (500 g, 2. 69 mol) in THF (200 Oml) ethanol (2000 ml) mixed solution with ice-cooling, calcium chloride (299 g, 2.69 mol) at the same temperature. Stir for 20 minutes. Next, sodium borohydride (102 g, 2.69 mol) was gradually added at room temperature, stirred at the same temperature for 3 hours, and further sodium borohydride (102 g, 2.69 mol) was added at room temperature. -Stirred. The reaction mixture was diluted with ethyl acetate (2000 ml) and poured into a 13% aqueous solution of ammonium chloride (1500 ml), and the precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (333 g, 87 %) Was obtained as a colorless solid.

'HNMR (300MHz, CDC1, 6 ppm): 3.45 (1Η, brs), 4.74 (2H, s), 7.25 (

Three

1H, d, J = 7.8Hz), 7.68 (1H, dd, J = 7.8, 2.4 Hz), 8.52 (1H, d, J = 2.4 Hz).

(6) Manufacture of (5-chloropyridine-2-yl) methyl methanesulfonate

To a THF (150 ml) solution of (5-chloro-pyridine-2-yl) methanol (12. 77 g, 88.9 mmol), triethylamine (12.4 ml, 88.9 mmol), methanesulfurol mouthride (6.9 ml, 88.9 mmol) was added and stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was recrystallized with a mixed solvent of ethyl acetate and diisopropyl ether to obtain the title compound (19.3 g, 98%) as a colorless solid. 'HNMR (400MHz, CDC1, 6 ppm): 3.11 (3Η, s), 5.31 (2H, s), 7.44 (1H

Three

, d, J = 8.4Hz), 7.75 (1H, dd, J = 8.4, 2.0 Hz), 8.57 (1H, d, J = 2.0 Hz)

(7) 4— [(5-Clopyridinepyridine 2-yl) methoxy] — 1— [4— (Tetrahydro- 1H-bilan-2-yloxy) phenol] pyridine— 2 (1H) —one Manufacturing of

4-Hydroxy 1— [4 (Tetrahydro 2H pyran-2-yloxy) phenol] pyridine— 2 (1H) ON (135 g, 470 mmol), potassium carbonate (130 g, 940 mmol) in DM F (2000 ml) at 80 ° C While stirring at 0, a DMF (1100ml) solution of (5-chloropyridine-2-yl) methyl methanesulfonate (125g, 564mmol) was added dropwise over 1 hour. The mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into water (10 L), and the precipitated solid was filtered and washed with water (1.5 L × 3 times). The obtained solid was dried at 50 ° C. under reduced pressure overnight to obtain a crude product of the title compound. The crude product was dissolved in black mouth form (500 ml) and concentrated gradually under reflux. When solid began to precipitate, the reflux was stopped and allowed to cool to room temperature, after which it was diluted with ethyl acetate (1000 ml). The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (160 g, 83%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.55— 1.75 (3Η, m), 1.82— 1.90 (2

Three

H, m), 1.95-2.05 (1H, m), 3.56— 3.64 (1H, m), 3.85— 3.93 (1H, m), 5.15 (2H, s), 5.45 (1H, t, J = 3.2Hz) , 6.02 (1H, d, J = 2.4Hz), 6.05 (1H, dd, J = 8.0, 3.2H), 7. 12 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

(8) 4 — [(5-Chromium pyridine-2-yl) methoxy] — 1— Production of (4-hydroxyphenol) pyridin-2- (1H) -one

4— [(5 Chlorocyclic pyridine-2-yl) methoxy] 1— [4 (Tetrahydro 2H-pyran—2-yloxy) phenol] pyridin-2- (1H) -one (160 g, 387 mmol) in ethanol (1200 ml ) Pyridinium p-toluenesulfonate (16.0 g, 63.7 mmol) was added to the solution and refluxed for 1 hour. The reaction solution was poured into water (10 L), and the precipitated solid was collected by filtration and washed with water. The title compound (126 g, 99%) was obtained as a colorless solid by drying under reduced pressure.

'HNMR (400MHz, CDC1, 6ppm): 5.18 (2Η, s), 6.08 (1H, d, J = 2.4Hz

Three

), 6.15 (1H, dd, J = 7.6, 2.8H), 6.62 (2H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.8Hz), 7.26 (1H, d, J = 8.0Hz) ), 7.44 (1H, d, J = 8.4Hz), 7.74 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

(9) Production of 1 (diphenylmethyl) 3-methyleneazetidine

1- (Diphenylmethyl) azetidine-3-ol (4.26 g, 17.8 mmol) in DMSO (50 ml) solution with triethylamine (24.8 ml, 178 mmol) and sulfur trioxide-pyridine complex (18.0 g, 113 mmol) And stirred at room temperature for 1 hour. Pour the reaction mixture into water and add ethyl acetate. And washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate.

. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (C—300, hexane: ethyl acetate = 3: 1) to give 1- (diphenylmethyl) azetidin-3-one colorless. Obtained as a solid. Next, to a solution of potassium tert-butoxide (6. Og, 5 3.5 mmol) in DMSO (lOOml) was added methyltriphenylphospho-bromide (19. lg, 53.5 mmol) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. Next, a solution of 1- (diphenylmethyl) azetidin-3-one in DMSO (20 ml) obtained above was added and stirred at 60 ° C. overnight. The reaction mixture was poured into water, extracted with jetyl ether, washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP—Sil, hexane: ethyl acetate = 40: 1) to obtain a crude product of the title compound. . The crude product was recrystallized from pentane (15 ml) to give the title compound (2.34 g, 56%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 3.77 (4Η, t, J = 2.4Hz), 4.47 (1H, s

Three

), 4.83—4.86 (2H, m), 7.15— 7.20 (2H, m), 7.21— 7.30 (4H, m), 7. 41-7.48 (4H, m).

(10) Manufacture of [1 (diphenylmethyl) azetidine 3-yl] methanol

Add 1- (diphenylmethyl) -1-3-methyleneazetidine (2.33 g, 9.9 mmol) in THF (2 Oml) with 0.5 mol ZL 9- BBN in THF (20.8 ml, 10.4 mmol) and add 2 at room temperature. Stir for hours. After cooling the reaction mixture with ice, ethanol (lml), 4N aqueous solution of sodium hydroxide and sodium chloride (6ml), and 30% hydrogen peroxide solution (6ml) were slowly added in order, and then at the same temperature for 10 minutes. Stir at room temperature for 4 hours. Water was added to the reaction solution, extraction was performed with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP—NH, hexane: ethyl acetate = 6: 1 to 4: 1) to give the title compound (1.8 g, 72%) was obtained as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 2.52— 2.60 (1Η, m), 2.98— 3.05 (2

Three

Η, m), 3.20— 3.28 (2Η, m), 3.80 (2H, d, J = 4.8Hz) 4.33 (1H, s), 7.1 5— 7.20 (2H, m), 7.21— 7.30 (4H, m) , 7.35—7.40 (4H, m). (11) Preparation of tert-butyl 3 (hydroxymethyl) azetidine 1 carboxylate [1- (diphenylmethyl) azetidine 1-yl] methanol (1. Og, 3.95 mmol) in methanol (30 ml) in 4N hydrochloric acid Ethyl acetate solution (2 ml) and palladium hydroxide (170 mg) were added, and the mixture was stirred at 67 PSI in a hydrogen atmosphere for 3 days. The reaction solution was filtered and concentrated under reduced pressure. The obtained residue was dissolved in THF (30 ml) and IN sodium hydroxide solution (10 ml), and (Boc) 2 O (0.95 g, 4.35 mmol) was stirred at room temperature for 3 hours. Add water to the reaction solution

2

The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP—Sil, hexane: ethyl acetate = 3: 1 to 1: 1), and the title compound (650111 ₈ , 88%) as a colorless oily liquid.

'HNMR (400MHz, CDC1, 6 ppm): 1.44 (9Η, s), 2.65— 2.75 (1H, m),

Three

3. 67— 3. 70 (2H, m), 3. 78 (2H, d, J = 6.8Hz), 4.00 (2H, t, J = 8.8Hz)

(12) 1— [4— (azetidine-3-ylmethoxy) phenol] 4— [(5-chloropyridine-2-yl) methoxy] pyridine-2 (1H) —one

tert Butyl 3 (hydroxymethyl) azetidine 1 To a solution of carboxylate (184 mg, 0.98 mmol) in THF (10 ml) was added triethylamine (150 1, 1.08 mmol) and methanesulfonyl chloride (76 1, 0.98 mmol). The mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to 4- [(5-cyclopentyl pyridine 1-2 yl) methoxy] 1- (4 hydroxyphenol) pyridine 1 2 (1H) -one (320 mg, 0.997 mmol), cesium carbonate (1.00 g, 3.07 mmol) and DMF (15 ml) were added, and the mixture was stirred at 80 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, 4N hydrochloric acid-ethyl acetate solution (5 ml) was added to the resulting residue, and the mixture was allowed to stand at room temperature for 1 hour. A 1N sodium hydroxide solution was added to the reaction solution to make the system alkaline, followed by extraction with black mouth form and drying over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel chromatography (KP—NH, chloroform-form: methanol = 90: 1 to 50: 1). This gave the title compound (140 mg, 36%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 3.13—3.22 (1Η, m), 3.55 (2Η, t, J

Three

= 7.6Hz), 3.80 (2H, t, J = 8. OHz), 4.15 (2H, d, J = 6.4Hz), 5.15 (2H, s), 6.01 (1H, d, J = 2.4Hz) , 6.08 (1H, dd, J = 7.6, 2.8Hz), 6.99 (2H, d

, J = 8.8Hz), 7.22-7.28 (3H, m), 7.44 (1H, d, J = 8.4Hz), 7.74 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 398, 400 (M + H)

[0122] In the following, the same procedure as in Example 1 was carried out except that (5-closed pyridine-2-yl) methyl methanesulfonate in Example 1- (7) was replaced with the following compounds.

2-4 compounds were obtained.

[0123] Example 2

1— [4— (azetidine-3-ylmethoxy) phenol] —4 — [(4 Fluorobenzyl) oxy] pyridine 2 (1H) —age

[0124] [Chemical 7]

4 The same operation as in Example 1 was carried out using fluorinated bendyl bromide to obtain the title compound (30 mg) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 3.13—3.22 (1Η, m), 3.50—3.60 (2

Three

Η, m), 3.75— 3.85 (2Η, m), 4.15 (2H, d, J = 6.4Hz), 4.99 (2H, s), 6. 01 (1H, d, J = 2.4Hz), 6.04 (1H , dd, J = 7.6, 2.8Hz), 6.99 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.20— 7.30 (3H, m), 7.40 (2H, dd , J = 8.8, 4.8Hz).

Mass spectrum (ESI): 381 (M + H)

[0125] Example 3

1— [4— (azetidine- ₃ —ylmethoxy) phenol] —4— [(4 benzyl) oxy] pyridine 2 (1H) —one [0126] [Chemical 8]

4 The same operation as in Example 1 was performed using black-opened benyl bromide to obtain the title compound (lOOmg) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 3.13—3.21 (1Η, m), 3.55 (2H, t, J

Three

= 8.4Hz), 3.80 (2H, t, J = 8.4Hz), 4.15 (2H, d, J = 6.4Hz), 5.00 (2H, s), 6.00-6.04 (2H, m), 6.99 (2H , d, J = 8.8Hz), 7.20— 7.27 (3H, m), 7.33-7.40 (4H, m).

Mass spectrum (ESI): 397, 399 (M + H)

[0127] Example 4

1— [4— (azetidine- ₃ —ylmethoxy) phenol] —4— [(3, 4 Diflurobenzene) oxy] pyridine 2 (1H) —one

[0128] [Chemical 9]

3,4 The title compound (118 mg) was obtained as a colorless solid in the same manner as in Example 1 using difluo-bend benzyl bromide.

'HNMR (400MHz, CDC1, 6ppm): 3.13—3.21 (1Η, m), 3.55 (2H, t, J

Three

= 8.0Hz), 3.80 (2H, t, J = 8.0Hz), 4.15 (2H, d, J = 6.4Hz), 4.98 (2H, s), 6.00— 6.04 (2H, m), 6.98 (2H , d, J = 8.8Hz), 7.10— 7.30 (6H, m) Mass spectrum (ESI): 399 (M + H)

Example 5

4— [((5-chloropyridine) -2-yl) methoxy] — 1— {4— [(1 Cyclopropylazeti Jin 3- ele * .l} pyridine 2 (1H) -one

[0130] [Chemical 10]

[4 (azetidine 3-ylmethoxy) phenol] —4— [(5 chloropyridine-2-yl) methoxy] pyridin 2 (1H) -one (47 mg, 0.12 mmol) in methanol (4 ml) Acetic acid (70 μ1), [(1 ethoxycyclopropyl) oxy] trimethylsilane (206 mg, 1.18 mmol) and sodium cyanoborohydride (74 mg, 1.18 mmol) were added, and the mixture was stirred at 50 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with black mouthform, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP—Sil, black mouth form: methanol = 10 0: 1 to 20: 1) to give the title compound (17 mg, 33 %) As a colorless solid

'HNMR (400MHz, CDC1, δ ppm): 0.32— 0.40 (4Η, m), 1.85— 1.91 (1

Three

Η, m), 2.86— 2.94 (1Η, m), 3.19 (2Η, t, J = 8. OHz), 3.52 (2H, t, J = 8. OHz), 4.09 (2H, d, J = 6.4Hz ), 5.15 (2H, s), 6.01 (1H, d, J = 2.4Hz), 6.08 (1H, dd, J = 7.6, 2.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.22— 7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 438, 440 (M + H)

[0131] Example 6

4— [(5 Chloropyridine 1-2-yl) methoxy] 1— {4— [(1 Isopropylazetidin 1 3-yl) methoxy] phenol} Pyridine 1 2 (1H) —On

[0132] [Chemical 11]

1— [4— (azetidine-3-ylmethoxy) phenol] 4— [(5-chloropyridine-2-yl) methoxy] pyridine 2 (1H) -one (37 mg, 0.09 mmol) in dichloromethane (4 ml ) Acetic acid (40 μ 1), acetone (40 μ 1) and sodium triacetoxyborohydride (62 mg, 0.27 mmol) were added to the solution, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with black mouthform and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP—Sil, black mouth form: methanol = 100: 1 to 20: 1) to give the title compound (29 mg, 71%) was obtained as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.96 (6Η, d, J = 6.4Hz), 2.33—2.4

Three

0 (1H, m), 2.88— 2.95 (1H, m), 3.07 (2H, t, J = 8. OHz), 3.46 (2H, t, J = 8. OHz), 4.10 (2H, d, J = 6.4Hz), 5.15 (2H, s), 6.01 (1H, d, J = 2.4 Hz), 6.08 (1H, dd, J = 7.6, 2.8Hz), 6.96 (2H, d, J = 8.8Hz), 7.22 — 7. 28 (3H, m), 7.43 (1H, d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4Hz), 8. 58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 440, 442 (M + H)

[0133] Example 7

4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Isopropylazetidine 1 3-yl) methoxy] phenol} pyridine 2 (1H) —one

[0134] [Chemical 12]

1— [4— (azetidine-3-ylmethoxy) phenol] —4 — [(4 Fluorobenzyl) The title compound was obtained as a colorless solid by the same operation as in Example 6 using oxy] pyridine 1 2 (1H) -one.

'HNMR (400MHz, CDC1, δ ppm): 0.98 (6Η, d, J = 6.4Hz), 2.38—2.4

Three

8 (1H, m), 2. 90- 2. 98 (1H, m), 3. 10— 3. 18 (2H, m), 3. 48— 3.57 (2H, m), 4. 10 ( 2H, d, J = 6.4Hz), 4.99 (2H, s), 6.00— 6.05 (2H, m), 6.96 (2H, d, J = 8.8Hz), 7 10 (2H, t, J = 8.8Hz), 7. 20— 7. 28 (3H, m), 7. 37- 7. 43 (2H, m).

Mass spectrum (ESI): 423 (M + H)

[0135] Example 8

1— [4— (azetidine— ₃ —yloxy) phenol] —4— [(4 fluorobenzyl) oxy] pyridine 2 (1H) —age

[0136] [Chemical 13]

(1) Preparation of tert-butyl 3-hydroxyazetidine 1-carboxylate 1-Fe-lethylamine (65.5 g, 0.54 mol) in a solution of epichlorohydrin (50. lg, 0.54 mol) in isopropanol (350 ml) Then, sodium hydrogen carbonate (68.2 g, 0.81 mol) was added, and the mixture was stirred for 8 hours while heating under reflux. The reaction mixture was filtered and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solvent under reduced pressure, L-tartaric acid (81.2 g, 0.54 mol) was dissolved in hot methanol (800 ml) with heating, and then palladium hydroxide (15. Og) was added to the resulting residue. The mixture was stirred for 2 days at 50 ° C under a hydrogen atmosphere (1 atm). Water (400 ml) was added to the reaction solution to dissolve the precipitated crystals, and then the reaction solution was filtered and concentrated under reduced pressure. Methanol (1000 ml) was added to the resulting residue, heated under reflux for 1 hour, and stirred overnight at room temperature. The precipitated crystals were filtered to obtain azetidine 3ol 'monotartrate (70. lg, 58%) as colorless crystals.

Azetidin-3-ol 'monotartrate (4.02 g, 18. Ommol) in THF (lOOml) (Boc) 0 (3.93 g, 18. Ommol) and IN sodium hydroxide aqueous solution (90 ml) were added to the liquid,

2

Stir vigorously at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the title compound (2.69 g, 86%) as a colorless oily liquid.

'HNMR (400MHz, CDC1, 6 ppm): 1.38 (9H, s), 3.60 (1H, s), 3, 77 (2H

Three

, dd, J = 8. 8, 4. 4Hz), 4.10 (2H, dd, J = 10. 4, 7. 2Hz), 4. 51-4.55 (1H, m).

(2) Production of tert butyl 3 [(methylsulfol) oxy] azetidine 1 carboxylate

tert-Butyl 3-hydroxyazetidine 1 Carboxylate (1.0 g, 5. 78 mmol) in THF (30 ml) in triethylamine (970 1, 6.96 mmol), methanesulfuryl chloride (446 1, 5.78 mmol ) And stirred for 30 minutes under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound (1.30 g, 90%) as a colorless oily liquid.

(3) Preparation of 1-[4- (azetidine 3-yloxy) phenol] -4 [(4 Fluorobenzyl) oxy] pyridine-2 (1H) -one

4 [(4 Fluorobenzyl) oxy] 1— (4 hydroxyphenol) pyridine 2 (1 H) one (1.00 g, 3.2 mmol), cesium carbonate (5.2 g, 16 mmol) in DMF (3 mL) At 80 ° C., a DMF (3 mL) solution of tert butyl 3 [(methylsulfoyl) oxy] azetidine 1 ruboxylate (1.30 g, 7.5 mmol) was added dropwise and stirred for 23 hours. Water was added to the reaction solution and filtered to obtain tert butyl 3- {4 [4 [(4 Fluorobenzyl) oxy] -2-oxoxopyridine 1 1 (2H) -yl] phenoxy} azetidine 1 1-carboxylate ( 1. 45 g, 97%) was obtained. To a methanol (10 ml) solution of this compound (1.45 g, 3. 1 mmol) was added 4N hydrochloric acid acetate solution (10 ml, 40 mmol), and the mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the solvent under reduced pressure was added 1N aqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was recrystallized with a mixed solvent of ethyl acetate and hexane, The title compound (1.12 g, 98%) was obtained as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 3.79— 3.84 (2Η, m), 3.92— 3.97 (2

Three

H, m), 4.98-5.05 (1H, m), 4.99 (2H, s), 6.02 (1H, dd, J = 7.6, 2.7H z), 6.04 (1H, d, J = 2.7Hz), 6.83 ( 2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.7Hz), 7.20 (1H, d, J = 7.6Hz), 7.25 (2H, d, J = 8.8Hz), 7.39 (2H , dd, J = 8.7, 5.2Hz).

Mass spectrum (ESI): 367 (M + H)

[0137] Example 9

4 [(4 Fluorobenzyl) oxy] 1 {4 [(1 Methylazetidine

Oxy] phenol} pyridine 2 (1H) -one

[0138] [Chemical 14]

1— [4— (azetidine-3-yloxy) phenol] —4 — [(4 fluorobenzyl) oxy] pyridin-2 (1H) -one (51.4 mg, 0.14 mmol), formalin aqueous solution (lml) and 0.3M A mixture of sodium cyanoborohydride monosalt-zinc (2-1) in methanol (lm L) was stirred at room temperature for 15 hours. A 1N aqueous sodium hydroxide solution was added to the reaction solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (KP— Sil FLASH12 + M, chloroform: methanol = 1: 0 to 4: 1), and the resulting crude product was acetic acid. Recrystallization from a mixed solvent of ethyl and heptane gave the title compound (46. lmg, 86%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 2.47 (3Η, s), 3.16—3.23 (2H, m),

Three

3.88— 3.99 (2H, m), 4.77—4.83 (1H, m), 4.99 (2H, s), 6.00— 6.04 (2H, m), 6.84 (2H, d, J = 9.3Hz), 7.10 (2H, t, J = 8.8Hz), 7.20 (1H, d, J = 7.3Hz), 7.25 (2H, d, J = 9.3Hz), 7.39 (2H, dd, J = 8.8, 5.4Hz). Mass spectrum (ESI ): 381 (M + H) [0139] Example 10

1— {4— [(1-Ethylazetidine 3 yl) oxy] phenol} 4— [(4 Fluorobenzyl) oxy] pyridine 2 (1H) —one

[0140] [Chemical 15]

The same operation as in Example 9 was carried out except that the formalin aqueous solution was replaced with acetonitrile (0.1 ml) to obtain the title compound (46.9 mg, 87%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.02 (3Η, t, J = 7.1Hz), 2.58 (2H, q

Three

, J = 7.1Hz), 3.07-3.13 (2H, m), 3.81— 3.88 (2H, m), 4.78—4.85 (1H, m), 4.99 (2H, s), 6.00— 6.04 (2H, m), 6.85 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.20 (1H, d, J = 7.3Hz), 7.25 (2H, d, J = 8.8Hz), 7.39 (2H, dd, J = 8.8, 5.4Hz).

Mass spectrum (ESI): 395 (M + H)

[0141] Example 11

1— {4— [(1 Cyclobutylazetidine 3 yl) oxy] phenol} 4— [(4 Fluorobenzyl) oxy] pyridine 2 (1H) —one

[0142] [Chemical 16]

The same operation as in Example 9 was carried out except that the formalin aqueous solution was changed to cyclobutanone (0.1 ml) in Example 9, and the title compound (52.3 mg, 90%) was obtained as a colorless solid. 'HNMR (400MHz, CDC1, 6ppm): 1.62—2.08 (6Η, m), 3.16—3.31 (3

Three

H, m), 3.72-3.88 (2H, m), 4.80—4.86 (1H, m), 4.99 (2H, s), 6.00 -6.04 (2H, m), 6.84 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.2 0 (1H, d, J = 7.8Hz), 7.25 (2H, d , J = 8.8Hz), 7.39 (2H, dd, J = 8.8, 5.1 Hz).

Mass spectrum (ESI): 421 (M + H)

[0143] Example 12

4— [(4-Fluorobenzyl) oxy] — 1— {4— [(1-Propylazetidine—3-yl) oxy] phenol} pyridine-2 (1H) —one

[0144] [Chemical 17]

1— [4 -— (azetidine-3-yloxy) phenol ”—4 -— [(4-Fluorobenzyl) oxy] pyridin-2 (1H) -one (53.8 mg, 0.15 mmol) in THF (lmL) solution Lopionaldehyde (0.1 ml) and sodium triacetoxyborohydride (124 mg, 0.59 mmol) were added and stirred at room temperature for 40 minutes. A 1N aqueous sodium hydroxide solution was added to the reaction solution, extracted with black mouth form, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (KP— Sil FLASH12 + M, black mouth form: methanol = 1: 0 to 4: 1), and the resulting crude product was acetic acid. Recrystallization from a mixed solvent of ethyl and heptane gave the title compound (51.4 mg, 86%) as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.92 (3Η, t, J = 7.4Hz), 1.37—1.45

Three

(2H, m), 2.46— 2.53 (2H, m), 3.06— 3.14 (2H, m), 3.81— 3.91 (2H, m), 4.78—4.85 (1H, m), 4.99 (2H, s), 6.01 (1H, dd, J = 7.6, 2.7Hz), 6.04 (1H, d, J = 2.7Hz), 6.84 (2H, d, J = 9.0Hz), 7.10 (2H, t, J = 8.8H z ), 7.20 (1H, d, J = 7.6Hz), 7.24 (2H, d, J = 9.0Hz), 7.39 (2H, dd, J = 8.8, 5.4Hz).

Mass spectrum (ESI): 409 (M + H)

[0145] Example 13 4— [(4 Fluorobenzyl) oxy] 1— {4— [(1-Isopropylazetidine-1-3-yl) oxy] phenol} pyridin-2 (1H) —one

[Chemical 18]

(1) Production of 1-isopropylazetidine 3-ol hydrochloride

Isopropylamine (247 ml, 2.90 mol) was added to a hexane (1000 ml) solution of epichlorohydrin (255. 5 g, 2.76 mol), and the mixture was stirred at room temperature for 2 days. After the solvent was concentrated under reduced pressure, acetonitrile (2000 ml) was added, and the mixture was stirred with heating under reflux for 5 hours. The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give the title compound (156.6 g, 37%) as colorless crystals.

'HNMR (400MHz, DMSO-d, 6 ppm): 1. 12 (6Η, d, J = 6. 8Hz), 3. 30—

6

3.36 (1H, m), 3.71- 3.77 (2H, m), 4.11--4.17 (2H, m), 4.32--4.40 (1H, m).

(2) 4— [(4 Fluorobenzyl) oxy] 1 {4 [(1 Isopropylazetidine 3 yl) oxy] phenol} Pyridine-2 (1H) —one

1 Isoethylazetidine 3-ol 'hydrochloride (97 mg, 0.64 mmol) in THF (5 ml) solution with triethylamine (180 1, 2.56 mmol), methanesulfuryl chloride (50 μ1, 0.64 mmol) And stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was added to 4 [(4 fluorobenzyl) oxy] 1- (4 hydroxyphenol) pyridin-2- (1H) -one (100 mg, 0.32 mmol), cesium carbonate ( 262 mg, 0.80 mmol) and DMF (3 ml) were added, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The title compound (75 mg, 57%) was obtained by purifying the residue obtained by concentrating the solvent under reduced pressure by silica gel column chromatography (C-300, black form: methanol = 90: 1 to 40: 1). Was obtained as a colorless solid. HNMR (400MHz, CDC1, δ ppm): 0.98 (6H, d, J = 6.4Hz), 2.39—2.4

Three

6 (1H, m), 3.08-3.13 (2H, m), 3.80— 3.86 (2H, m), 4.75—4.81 (1H, m), 4.99 (2H, s), 6.01 (1H, d, J = 2.4 Hz), 6.02— 6.04 (1H, m), 6.8 5 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7.20 (1H, d, J = 7.2Hz), 7.24 (2H, d, J = 8.8Hz), 7.39 (2H, dd, J = 8.8, 4.8Hz).

Mass spectrum (ESI): 409 (M + H)

[0147] Example 14

1— [4— (Zazetidine— ₃ —yloxy) phenol] 4 — [(5 — Chlorocyclic pyridine-2-yl) methoxy] pyridine 2 (1H) —one

[0148] [Chemical 19]

In Example 8 (3) 4-[(4 fluorobenzyl) oxy] — 1- (4 hydroxyphenol) pyridin 2 (1H) -one was replaced with the corresponding compound, and the same procedure was followed. The title compound (737 mg, 75%) was obtained as a colorless solid.

'HNMR (400MHz, DMSO-d, 6ppm): 3.97—4.01 (2Η, m), 4.41—4.

6

47 (2H, m), 5.10— 5.17 (1H, m), 5.24 (2H, s), 5.97 (1H, d, J = 2.8Hz), 6.14 (1H, dd, J = 7.6, 2.8Hz), 6.97 (2H, d, J = 8.8Hz), 7.34 (2H, d, J = 8.8Hz), 7.56 (1H, d, J = 7.6Hz), 7.62 (1H, d, J = 7.6Hz), 8.04 (1 H, dd, J = 8.8, 2.8Hz), 8.70 (1H, d, J = 2.8Hz).

Mass spectrum (ESI): 384, 386 (M + H)

[0149] Example 15

4 — [(5 Chloropyridine pyridine-2-yl) methoxy] — 1— {4— [(1-Methylazetidine-3-yl) oxy] phenol} pyridine-2 (1H) -one

[0150] [Chemical 20]

1— [4— (azetidine-3-yloxy) phenol] 4— [(5 2-chloro) pyridine] 2] (1H) -one (70 mg, 0.18 mmol) in dichloromethane (3 ml ) Acetic acid (30 1), formalin aqueous solution (100 1) and sodium triacetoxyborohydride (77 mg, 0.36 mmol) were added to the solution and stirred at room temperature for 3 hours. To the reaction solution was added 0.5N aqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous sodium sulfate. The title compound (51 mg, 70%) was purified by purifying the residue obtained by concentrating the solvent under reduced pressure by silica gel column chromatography (KP-Si, chloroform: methanol = 100: 1 to 20: 1). Obtained as a solid.

'HNMR (400MHz, CDC1, 6ppm): 2.43 (3Η, s), 3.12— 3.18 (2H, m),

Three

3.83— 3.90 (2H, m), 4.75—4.81 (1H, m), 5. 14 (2H, s), 6.01 (1H, d, J = 2.8Hz), 6.07 (1H, dd, J = 7.6, 2.8 Hz), 6.84 (2H, d, J = 8.8Hz), 7. 20-7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4 Hz ), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 398, 400 (M + H)

[0151] Example 16

4— [(5 Chloropyridine 2 yl) methoxy] 1— {4— [(1 Ethenoreazetidine 3 yl) oxy] phenol} pyridine-2 (1H) —one

[0152] [Chemical 21]

The title compound (4 Omg, 53%) was obtained as a colorless solid by the same operation as in Example 15 using acetoaldehyde.

'HNMR (400MHz, CDC1, 6ppm): 1.01 (3Η, t, J = 7.2Hz), 2.56 (2H, q , J = 7.2Hz), 3.06-3.12 (2H, m), 3.80— 3.86 (2H, m), 4.77—4.84 (1H, m), 5.15 (2H, s), 6.01 (1H, d, J = 2.8 Hz), 6.07 (1H, dd, J = 7.6, 2.8Hz), 6.84 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz) , 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass Spectrum (ESI): 412, 414 (M + H)

[0153] Example 17

4— [(5-Chronic pyridine-2-yl) methoxy] — 1— {4-— [(1-Propylazetidine-1-3-yl) oxy] phenol} pyridine 1 2 (1H) — ON

[0154] [Chemical 22]

The same operation as in Example 15 was carried out using propionaldehyde to give the title compound (49 mg, 63%) as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.92 (3Η, t, J = 7.2Hz), 1.37—1.45

Three

(2H, m), 2.49 (2H, t, J = 7.2Hz), 3.07— 3.13 (2H, m), 3.82— 3.88 (2 H, m), 4.77-4.84 (1H, m), 5.15 ( 2H, s), 6.01 (1H, d, J = 2.8Hz), 6. 07 (1H, dd, J = 7.6, 2.8Hz), 6.84 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H , m), 7.43 (1H, d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 426, 428 (M + H)

[0155] Example 18

4— [(5-Chronic pyridine-2-yl) methoxy] — 1— {4-— [(1-Isopropylazetidin-1-3-yl) oxy] phenol} Pyridine 1 2 (1H) —On

[0156] [Chemical 23]

The same operation as in Example 15 was carried out using acetone to obtain the title compound (28 mg, 53%) as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.98 (6Η, d, J = 6.4Hz), 2.38—2.4

Three

5 (1H, m), 3.08-3.13 (2H, m), 3.80— 3.85 (2H, m), 4.75—4.81 (1H, m), 5.14 (2H, s), 6.01 (1H, d, J = 2.8 Hz), 6.07 (1H, dd, J = 7.6, 2.8 Hz), 6.85 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz) , 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 426, 428 (M + H)

[0157] Example 19

4— [(5-Cyclopentylpyridine-2-yl) methoxy] — 1— {4-— [(1-Cyclobutylazetidin-3-yl) oxy] phenol} Pyridine 1 2 (1H ) —On

[0158] [Chemical 24]

The same operation as in Example 15 was performed using cyclobutanone to give the title compound (30 mg, 53%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.60—1.92 (4Η, m), 1.94—2.05 (2

Three

H, m), 3.15-3.26 (3H, m), 3.72— 3.78 (2H, m), 4.77—4.83 (1H, m), 5.14 (2H, s), 6.01 (1H, d, J = 2.4Hz) , 6.07 (1H, dd, J = 7.6, 2.4Hz), 6.84 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H, m), 7.43 (1H, d, J = 8.4Hz), 7.72 ( 1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 438, 440 (M + H)

[0159] Example 20

4 — [(5-Chromium pyridine-2-yl) methoxy] — 1— (4— {[1— (2-Fluoroethyl) azetidin-3-yl] oxy} phenol) pyridine-2 (1H) —On

[0160] [Chemical 25] ^Ρ

1— [4— (azetidine- ₃ —yloxy) phenol] — 4 [(5-Cyloxypyridine-2-yl) methoxy] pyridin-2 (1H) -one (90 mg, 0.23 mmol) DMF ( 4 ml) solution was charged with potassium carbonate (100 mg, 0.72 mmol) and 2 fluoroethyl trifluoromethanesulfonate (70 mg, 0.36 mmol) and stirred at 60 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The title compound (35 mg, 35%) was obtained by purifying the residue obtained by concentrating the solvent under reduced pressure by silica gel column chromatography (KP—Sil, chloroform: methanol = 100: 1 to 20: 1). Obtained as a colorless solid.

'HNMR (400MHz, CDC1, Sppm): 2.84 (2Η, dt, J = 28.3, 5.0Hz), 3.2

Three

2— 3.27 (2H, m), 3.91— 3.96 (2H, m), 4.49 (2H, dt, J = 47.3, 5.0Hz), 4.80—4.86 (1H, m), 5.15 (2H, s), 6.01 ( 1H, d, J = 2.4Hz), 6.07 (1H, dd, J = 7.6, 2.4Hz), 6.84 (2H, d, J = 8.8Hz), 7.20— 7.28 (3H, m), 7.43 (1H , d, J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 430, 432 (M + H)

[0161] Example 21

l- (4-{[(2S) 2 azetidine 1-propylpropyl] oxy} phenyl) -4 [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one

[0162] [Chemical 26]

(1) Preparation of (2R) -2- (Tetrahydro-1H-pyran-2-yloxy) propane-1-ol (R) —Methyl lactate (49.6 g, 476 mmol) in chloroform (500 ml) was added to pyridinium p-toluenesulfonate (12. Og, 47.7 mmol), 3, 4 dihydro-2H-pyran (48 0 ml, 526 mmol) was sequentially added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain methyl (2R) -2- (tetrahydro-2H-pyran-2-yloxy) propanate (88.6 g, 99%) as a colorless liquid. Next, to a solution of lithium aluminum hydride (12.5 g, 329 mmol) in THF (400 ml) under ice-cooling, methyl (2R) -2- (tetrahydro 2H pyran-2-yloxy) propanate (88 (6 g, 470 mmol) in THF (150 ml) was added dropwise over 30 minutes, and then the reaction solution was heated to reflux for 3 hours. After cooling the reaction solution to 0 ° C, water (12.5 ml) was slowly added dropwise, then 15% aqueous sodium hydroxide solution (12.5 ml) and water (37.5 ml) were added successively, and THF (lOOml) And stirred at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure (bp: 66—72 ° C Zl. 0-1.4 to rr) to give the title compound (65.8 g, 86 %, 1: 1 diastereomeric mixture) was obtained as a colorless liquid.

'HNMR (400MHz, CDC1, 6 ppm): 1.13 (1.5Η, d, J = 6.4Hz), 1.22 (1.

Three

5H, d, J = 6.4Hz), 1.45— 1.64 (4H, m), 1.70—1.90 (2H, m), 3.43—3.70 (3H, m), 3.78—4.0.2 (2H, m), 4. 53—4.58 (0.5H, m), 4.70—4.75 (0.5H, m).

(2) (2R)-2- (Tetrahydro-1H-pyran-2-yloxy) propyl methanesulfonate

(2R) — 2— (Tetrahydro 2H-pyran-2-yloxy) propane 1 ol (1.51 g, 9.4 mmol) in THF (30 ml) solution [0 ^o C [trote tritinoremine (2.6 ml, 19 mmol) and methanesulfur chloride (0.877 ml, l mmol) were added and stirred at the same temperature for 30 minutes. Ethyl acetate was added to the reaction solution, washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure is purified by silica gel column chromatography (KP— Sil FLASH25 + M, ethyl acetate: hexane = 0: 1 to 4: 1). (2R) -2- (tetrahydro-1 2H-pyran-2-yloxy) propyl methanesulfonate (2.14 g, 95%, 1: 1 diastereomeric mixture) was obtained.

'HNMR (400MHz, CDC1, 6ppm): 1.23 (1.5Η, d, J = 6.4Hz), 1.30 (1.

Three

5H, d, J = 6.4Hz), 1.50—1.63 (4H, m), 1.70—1.86 (2H, m), 3.05 (1.5H, s), 3.08 (1.5H, s), 3.49—3.56 (1H , m), 3.86- 3.95 (1H, m), 4.04-4.26 (3H, m), 4.71-4.77 (1H, m).

(3) 4— [(4 Fluorobenzyl) oxy] 1 1 1 (4 1 {[(2R) — 2 Hydroxypropyl] oxy} phenol) Preparation of 2 (1H) —one

(2R) -2- (Tetrahydro-2H-pyran-1-yloxy) propyl methanesulfonate obtained above, 4-[(4-Fluorobenzyl) oxy] -1- (4-hydroxyphenyl) pyridine— Using 2 (1H) one (1. OOg, 3.2 mmol), the same procedure as in Example 8 (3) was performed, and the resulting crude product was subjected to silica gel column chromatography (KP— Sil FLASH 25 + M, chlorohonorem). : Methanolol = 1: 0 to 9: 1) and purified with 4 [(4 fluobenzene) oxy] 1— (4— {[(2R) — 2 (tetrahydro 2H pyran 2 yloxy) pill] Oxy} (phenyl) pyridin 2 (1H) -one (1.46 g, 100%) was obtained. Next, the obtained 4-[(4 fluorobenzyl) oxy] 1- (4— {[(2R) -2 (tetrahydric 2-H-pyran-2-yloxy) propyl} oxy} phenol) pyridine 2 (1H) A solution of ethanol (1.41 g, 3. 1 mmol) and pyridinium p-toluenesulfonate (0.39 g, 1.6 mmol) in ethanol (6 ml) was heated to reflux for 1 hour. Water was added to the reaction solution, and the crude product obtained by filtration was purified by silica gel column chromatography (KP— Sil FLASH25 + M, chloroform: methanol = 1: 0 to 9: 1), and 4 — [(4 Fluorobenzyl) oxy] — 1— (4— {[(2R) — 2 hydroxypropyl] oxy} phenyl) pyridine 1 2 (1H) —one (840 mg, 73%) was obtained.

'HNMR (400MHz, CDC1, 6ppm): 1.29 (3Η, d, J = 6.4Hz), 3.83 (1H, d

Three

d, J = 9.3, 7.3Hz), 3.96 (1H, dd, J = 9.3, 3.4Hz), 4.17—4.25 (1H, m), 4.99 (2H, s), 6.00—6.05 (2H, m), 6.95 — 7.00 (2H, m), 7.05— 7.1 4 (2H, m), 7.20-7.29 (3H, m), 7.36— 7.42 (2H, m).

(4) (1R) — 2— {4— [4— (4 Fluorobenzyl) oxy] 2 -oxopyridine 1 ( 2H) —yl] phenoxy}-1-methylethyl 4-methylbenzenesulfonate 4 [(4 fluorobenzyl) oxy] 1— (4— {[(2R) — 2 hydroxypropyl] oxy} phenol) pyridine — 2 (1H) -one (833 mg, 2.3 mmol), p Toluenesulfonyl chloride (1.3 g, 6.8 mmol), Dimethylaminopyridine (55 mg, 0.45 mmol) and Triethylamine (0.94 ml, 6.8 mmol) The mouth form (10 ml) solution was stirred at 50 ° C. for 7 hours. Ethyl acetate was added to the reaction solution and filtered, and the obtained filtrate was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel chromatography (KP— Sil FLASH25 + M, black mouth form: methanol = 1: 0 to 9: 1) to obtain (1R) — 2— {4 1 [4 1 (4 1 Fluorobenzyl) oxy] 1 2 -oxopyridine 1 1 (2H) -yl] phenoxy} -1-methylethyl 4-methylbenzensulfonate (1.12 g, 95%) was obtained.

'HNMR (400MHz, CDC1, 6ppm): 1.43 (3Η, d, J = 6.8Hz), 2.45 (3H, s

Three

), 3.93 (1H, dd, J = 10.2, 4.4Hz), 4.03 (1H, dd, J = 10.2, 5.8Hz), 4.84-4.92 (1H, m), 4.99 (2H, s), 5.98— 6.04 (2H, m), 6.78 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8Hz), 7. 16— 7.25 (3H, m), 7.31— 7.41 (4 H, m ), 7.82 (2H, d, J = 8.4Hz).

(5) 1— (4— {[(2S) — 2 azetidine mono-1-propyl) oxy} -vinyl) -4-one [(4 fluorobenzyl) oxy] pyridine 2 (1H) Preparation of 1

(1R) — 2— {4 [4 (4-fluorobenzyl) oxy] 2 -oxopyridine 1 (2 H) yl] phenoxy} 1 methylethyl 4 methylbenzenesulfonate (102 mg, 0.20 mmol) and azetidine (0.2 ml) The DMF (0.4 ml) solution was stirred at 60 ° C for 2 days. Water was added to the reaction solution, filtered, and purified by preparative thin-layer silica gel chromatography (KieselgelTM 60F254, black mouth form: methanol: aqueous ammonia = 10: 1: 0.1). The crude product obtained was purified by acetic acid. Recrystallization from a mixed solvent of ethyl and heptane gave the title compound (45.6 mg, 57%) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.06 (3Η, d, J = 6.3Hz), 2.05— 2.1

Three

3 (2H, m), 2.65— 2.72 (1H, m), 3.27— 3.38 (4H, m), 3.75— 3.80 (1H , m), 3.85-3.90 (1H, m), 4.99 (2H, s), 6.01 (1H, dd, J = 7.6, 2.7Hz), 6.04 (1H, d, J = 2.7Hz), 6.96 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8 Hz), 7.21 (1H, d, J = 7.6Hz), 7.24 (2H, d, J = 8.8Hz), 7.39 (2H, dd, J = 8.8, 5.4Hz).

Mass spectrum (ESI): 409 (M + H)

[0163] Example 22

-(4-{[(2R) 2 azetidine 1-ylpropyl] oxy}

-Fluorobenzyl) oxy] pyridine 2 (1H) —one

[0164] [Chemical 27]

(1) (2S) — Preparation of 2- (tetrahydro 2H-pyran 2-yloxy) propane 1 ol

(S) -Methyl lactate (39. Og, 375 mmol) was used in the same manner as in Example 21 (1) to give the title compound (51.7 g, 86%, 1: 1 diastereomeric mixture) colorless. Obtained as a liquid (bp: 73-79 ° C Zl.8-2.2torr).

'HNMR (400MHz, CDCl, 6ppm): 1.13 (1.5H, d, J = 6.4Hz), 1.22 (1.

Three

5H, d, J = 6.4Hz), 1.45— 1.64 (4H, m), 1.70—1.90 (2H, m), 3.43— 3.70 (3H, m), 3.78—4.02 (2H, m), 4.53— 4.58 (0.5H, m), 4.70-4.7 5 (0.5H, m).

(2) 1— (4— {[(2R) —2 azetidine— 1-ylpropyl] oxy} phenyl) 4— [(4 fluorobenzyl) oxy] pyridine 2 (1H) Preparation of 1

(2S) -2- (Tetrahydro-2H-pyran-2-yloxy) propan-1ol was used in the same manner as in Example 21 (2) to (5) to give the title compound (42 mg) as a colorless solid. Got as.

'HNMR (400MHz, CDCl, 6ppm): 1.06 (3Η, d, J = 6.3Hz), 2.06— 2.1 4 (2H, m), 2.65-2.72 (1H, m), 3.28— 3.38 (4H, m), 3.75— 3.80 (1H, m), 3.86-3.91 (IH, m), 4.99 (2H, s), 6.01 (IH, dd, J = 7.3, 2.7Hz), 6.04 (IH, d, J = 2.7Hz), 6.96 (2H, d, J = 8.8Hz), 7.10 (2H, t, J = 8.8 Hz), 7.21 (IH, d, J = 7.3Hz), 7.24 (2H, d, J = 8.8Hz), 7.39 (2H, dd, J = 8.8, 5.4Hz).

Mass spectrum (ESI): 409 (M + H)

[0165] Example 23

1 (4 {[((2S) —2azetidine 1-propyl) oxy}

1-yl) methoxy] pyridine 1 2 (1H) -one

[0166] [Chemical 28]

4-[[(5-chloropyridine) -2-yl) methoxy] — 1- (4 hydroxyphenol) pyridin — 2 (1H) -one was used in the same manner as in Example 21 to obtain the title. Compound (8 mg) was obtained as a colorless solid.

'HNMR (400MHz, CDCl, 6ppm): 1.09 (3Η, d, J = 6.3Hz), 2.08— 2.1

Three

8 (2H, m), 2.71-2.80 (1H, m), 3.32—3.46 (4H, m), 3.77—3.96 (2H, m), 5.14 (2H, s), 6.01 (IH, d, J = 2.7 Hz), 6.07 (1H, dd, J = 7.6, 2.7 Hz), 6.96 (2H, d, J = 9. OHz), 7.22— 7.26 (3H, m), 7.43 (IH, d, J = 8.3 Hz) ), 7.73 (1H, dd, J = 8.3, 2.4Hz), 8.58 (IH, d, J = 2.4Hz).

Mass spectrum (ESI): 426, 428 (M + H)

[0167] Example 24

-(4-{[(2R) 2 azetidine 1-ylpropyl] oxy}

1-yl) methoxy] pyridine 1 2 (1H) -one

[0168] [Chemical 29]

4-[[(5-chloropyridine) -2-yl) methoxy] — 1- (4 hydroxyphenol) pyridin — 2 (1H) -one was used in the same manner as in Example 22 to obtain the title. Compound (23 mg) was obtained as a colorless solid.

'HNMR (400MHz, CDCl, 6ppm): 1.07 (3Η, d, J = 6.3Hz), 2.07— 2.1

Three

6 (2H, m), 2.66— 2.75 (1H, m), 3.29— 3.42 (4H, m), 3.76— 3.93 (2H, m), 5.14 (2H, s), 6.01 (1H, d, J = 2.7 Hz), 6.07 (1H, dd, J = 7.6, 2.7 Hz), 6.96 (2H, d, J = 9.0Hz), 7.22-7.25 (3H, m), 7.43 (1H, dd, J = 8.5, 0.6Hz), 7.73 (1H, dd, J = 8.5, 2.4Hz), 8.58 (1H, dd, J = 2.4, 0.6 Hz).

Mass spectrum (ESI): 426, 428 (M + H)

[0169] Example 25

1— {4— [(2S) -azetidine mono-2-ylmethoxy] phenol} — 4-— [(5-chloropyridine 2-yl) methoxy] pyridine 2 (1H) —one

[0170] [Chemical 30]

tert Butyl (2S) — 2 (hydroxymethyl) azetidine 1 carboxylate, 4 — [(5 cyclopyridine pyridine 2-methoxy)] 1 — (4 hydroxyphenol) pyridine 1 2 (1H) —one The title compound (276 mg) was obtained as a colorless solid by the same operations as in Example 8 (2) to (3).

'HNMR (400MHz, CDCl, 6ppm): 2.21— 2.30 (1Η, m), 2.36— 2.45 (1

Three

Η, m), 3.39— 3.52 (1 Η, m), 3.66— 3.86 (1 Η, m), 3.95—4.31 (3 Η, m), 5.15 (2H, s), 6.02 (1H, d, J = 2.7 Hz) , 6.07 (1H, dd, J = 7.6, 2.7Hz) , 6.99 (2H, d, J = 9.0Hz), 7.22— 7.26 (3H, m), 7.43 (1H, d, J = 8.5Hz), 7.73 (1H, dd, J = 8.5, 2.4Hz), 8.58 ( (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 398, 400 (M + H)

[0171] Example 26

4— [(5 Chloropyridine—2-yl) methoxy] 1— (4— {[(2S)-1-Methylazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) —one

[0172] [Chemical 31]

The title compound (17 mg) was obtained as a colorless solid by performing the same operation as in Example 12 using a formalin aqueous solution.

'HNMR (400MHz, CDC1, 6ppm): 2.04— 2.16 (2Η, m), 2.42 (3H, s),

Three

2.84— 2.95 (1H, m), 3.36— 3.54 (2H, m), 3.97—4.10 (2H, m), 5.14 (2H, s), 6.01 (1H, d, J = 2.7Hz), 6.07 (1H, dd, J = 7.6, 2.7Hz), 6.98 (2H, d, J = 9.0Hz), 7.23 (1H, d, J = 7.6Hz), 7.24 (2H, d, J = 9.0Hz), 7. 43 ( 1H, d, J = 8.3Hz), 7.73 (1H, dd, J = 8.3, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass Spectrum (ESI): 412, 414 (M + H)

[0173] Example 27

4 [(5 Chloropyridine 2 yl) methoxy] 1 1 (4 {[(2S) 1 Ethylazetidine 2-yl] methoxy} phenol) pyridine 2 (1H) -one

[0174] [Chemical 32]

The title compound (6m) was prepared by carrying out the same operation as in Example 12 using acetaldehyde. g) was obtained as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.97—1.09 (3Η, m), 2.04— 2.20 (2

Three

Η, m), 2.41-2.52 (1Η, m), 2.72— 2.91 (2Η, m), 3.41— 3.57 (2H, m), 3.98-4.09 (2H, m), 5.14 (2H, s), 6.01 ( 1H, d, J = 2.7Hz), 6.07 (1 H, dd, J = 7.6, 2.7Hz), 6.97 (2H, d, J = 9. OHz), 7.22— 7.27 (3H, m), 7.43 (1H , d, J = 8.5Hz), 7.73 (1H, dd, J = 8.5, 2.4Hz), 8.58 (1H, d, J = 2.4Hz).

Mass spectrum (ESI): 426, 428 (M + H)

[0175] Example 28

4— [(5 Chloropyridine—2-yl) methoxy] 1— (4— {[(2S)

1-yl] methoxy} phenyl) pyridine 2 (1H) -one

[0176] [Chemical 33]

The title compound (llmg) was obtained as a colorless solid by the same procedures as in Example 12 using propionaldehyde.

'HNMR (400MHz, CDC1, δ ppm): 0.90 (3Η, t, J = 7.3Hz), 1.37—1.49

Three

(2H, m), 2.04— 2.18 (2H, m), 2.32— 2.44 (1H, m), 2.60— 2.71 (1H, m), 2.80— 2.92 (1H, m), 3.40— 3.53 (2H, m) , 3.96—4.11 (2H, m), 5.14 (2H, s), 6.01 (1H, d, J = 2.7Hz), 6.07 (1H, dd, J = 7.6, 2.7Hz), 6.97 (2H , d, J = 9. OHz), 7.23 (1H, d, J = 7.6Hz), 7.24 (2H, d, J = 9. OHz), 7.43 (1H, dd, J = 8.3, 0.7Hz), 7.73 (1H, dd, J = 8.3, 2.4Hz), 8.58 (1H, dd, J = 2.4, 0.7Hz).

Mass spectrum (ESI): 440, 442 (M + H)

[0177] Example 29

4— [(5-Chromium pyridine-2-yl) methoxy] 1— (4— {[(2S)-1-isopropyl Zetidine 2—yl] methoxy} phenol) pyridine 1 2 (1H) —one

[0178] [Chemical 34]

The same operation as in Example 9 was carried out using acetone to obtain the title compound (26 mg) as a colorless solid.

'HNMR (400MHz, CDC1, δ ppm): 0.96 (3Η, d, J = 6.3Hz), 1.03 (3H, d

Three

, J = 6.3Hz), 1.98— 2.08 (1H, m), 2.11— 2.20 (1H, m), 2.44— 2.53 (1H, m), 2.88— 2.96 (1H, m), 3.42— 3.58 (2H, m ), 3.97—4.02 (1H, m), 4.07—4.13 (1H, m), 5. 15 (2H, s), 6.02 (1H, d, J = 2.7Hz), 6.07 (1H, dd, J = 7.6 , 2.7Hz), 6.96 (2H, d, J = 9.0Hz), 7.23 (1H, d, J = 7.6Hz), 7.24 (2H, d, J = 9.0Hz), 7.43 (1H, dd, J = 8.4 , 0.6Hz), 7.73 (1H, dd, J = 8.4, 2.6Hz), 8.58 (1H, dd, J = 2.6, 0.6Hz).

Mass spectrum (ESI): 440, 442 (M + H)

[0179] Example 30

4 [(5 Chloropyridine 2 yl) methoxy] 1 4 {[(2S) 1-Cyclobutyl azetidine 2-yl] methoxy} phenol) pyridine 2 (1H) -one

[0180] [Chemical 35]

The same operation as in Example 9 was performed using cyclobutanone to obtain the title compound (21 mg) as a colorless solid.

'HNMR (400MHz, CDC1, 6ppm): 1.61— 1.75 (2Η, m), 1.82— 2.13 (6

Three

H, m), 2.96— 3.05 (1H, m), 3.16— 3.37 (2H, m), 3.49— 3.61 (1H, m), 3.94—4.07 (2H, m), 5.15 (2H, s), 6.01 ( 1H, d, J = 2.7Hz), 6.07 (1 H, dd, J = 7. 5, 2. 7Hz), 6. 95 (2H, d, J = 9. OHz), 7. 22— 7. 27 (3H, m), 7. 43 (1H, d , J = 8.4Hz), 7.73 (1H, dd, J = 8.4, 2.3Hz), 8.58 (1H, d, J = 2.3Hz).

Mass spectrum (ESI): 452, 454 (M + H)

Industrial applicability

The compound of the present invention has MCH-1R antagonistic activity, excellent metabolic stability, high safety, excellent in vivo anti-obesity activity, and excellent balance as a medicine. Therefore, metabolic diseases such as obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, such as angina pectoris, acute congestive heart failure, myocardial infarction, cyclic arteriosclerosis Circulatory system diseases such as hypertension, hypertension, kidney disease, electrolyte abnormalities such as bulimia, affective disorder, depression, anxiety, hemorrhoids, delirium, dementia, schizophrenia, attention deficit / hyperactivity disorder, memory impairment, sleep Disorders, cognitive impairments, movement disorders, sensory abnormalities, olfactory disturbances, morphine tolerance, narcotic addiction, alcohol dependence, and other central and peripheral nervous system diseases such as infertility, premature birth, reproductive system diseases such as sexual dysfunction, etc. It is useful as a prophylactic or therapeutic agent for gastrointestinal diseases, respiratory diseases, cancer or skin pigmentation.

Claims

The scope of the claims

[Where

Az optionally has a substituent and may represent a azetidyl group; L represents a single bond or optionally a substituent and may represent a C1-C2 alkylene group, provided that When L is a single bond, L is not bonded at the 1- or 2-position of the azetidyl group, and when L is a methylene group, L is not bonded at the 1-position of the azetidyl group.

A 1-phenylbilidone derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

[2] The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Az is an unsubstituted azetidyl group.

[3] Az substituent may be optionally substituted with a fluorine atom or a hydroxyl group C1

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a -C4 alkyl group, or optionally substituted with a fluorine atom or a hydroxyl group, and is a V, C3-C4 cycloalkyl group.

[4] The compound according to any one of claims 1 to 3, wherein L is a single bond, or a pharmaceutically acceptable salt thereof.

[5] The force according to any one of claims 1 to 3, wherein L is an unsubstituted methylene group, or optionally substituted with a C1-C4 alkyl group! A compound or a pharmaceutically acceptable salt thereof.

[6] Ar force A phenol group optionally substituted by 1 or 2 halogen atoms. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

[7] Ar force The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a pyridyl group optionally substituted by 1 or 2 halogen atoms.

[8] The compound represented by the formula (I) is

4— [(5 Chloropyridine 1-yl) methoxy] 1— {4— [(1 Propylazetidine 1

3yl) oxy] phenyl} pyridin-2 (1H) -one,

4— [(5 Chlorocyclic pyridine-2-yl) methoxy] 1— {4 -— [(1 Isopropylazetidin-1 yl) oxy] phenol} Pyridine 1 2 (1H) —one,

l-(4- {[((2S) 2 azetidine 1-propyl) oxy} phenyl) -4 [(4 fluorobenzyl) oxy] pyridine 2 (1H) —one,

4 1 [(5 Chloropyridine 1 2-yl) methoxy] 1 1 1 (4 1 {[(2S) 1 1 1 Ethylazetidine 2-yl] methoxy} -phenyl) pyridine 2 (1H) -one, as well as

4— [(5 Chloropyridine pyridine 2-yl) methoxy] 1— (4— {[(2S)-1-Isopropylzetidine 2-yl] methoxy} phenol) pyridine 1 2 (1H) — 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein a group power consisting of ON is also selected.

[9] Compound force represented by the formula (I) 1 {4 [(1 ethylazetidine-3 yl) oxy] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4- (4- (benzylfluoro) oxy] pyridin-2- (1H) -one.

[10] Compound force represented by the formula (I) 4 [(4 fluorobenzyl) oxy] 1 {4 [(1 isopropylazetidine 3 yl) oxy] phenol-pyridine} pyridine 2 (1H) ON, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

[11] The compound represented by the formula (I) is 1 [4 (azetidine 3-yloxy) phenol] 4 — [(5 Chloropyridine-2-yl) methoxy] pyridine-2 (1H) -one The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

[12] Compound power represented by the formula (I) 4 [(5 black pyridine 2-yl) methoxy] 1 {4

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is [(1 ethylazetidine 3-yl) oxy] phenyl} pyridine 2 (1H) one.

[13] Compound power represented by the formula (I) 4 [(5 black pyridine 2-yl) methoxy] 1 {4

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is [(1 isopropylazetidine 3 yl) oxy] phenol} pyridine 2 (1H) -one.

[14] Compound Power Represented by Formula (I) 4 [(5 Chloropyridine 2 yl) Methoxy] 1 1 (4 1 {[(2S) — 1 Ethylazetidine 2 yl] Methoxy} File) 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof which is pyridine 2 (1H) one.

[15] A melanin-concentrating hormone receptor antagonist comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

[16] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

[17] The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, simvastatin; mepastatin; ezetimibe; atorvastatin; sitagribtin ( metformin; sibutramine; orlistat; knexa; topiramate; topiramate; phentermine; losartan; Losartan combined with thiazide hydrochloride Agent; rimonabant, N— [3— (4-chlorophenol) 2 (S) —Fuel 1 (S) —methylpropyl] — 2— (4-trifluoromethyl) (Tyru-2-pyrimidyloxy) 2 methylpropanamide, N- [(1S, 2S) -3- (4 black-mouthed) 2- (3-cyanophyl) 1-methylpropyl] — 2-methyl 2— { [5 (Trifluoromethyl) pyridine 2yl] oxy} propanamide, N— [3— (4 Black-mouthed Fu-Nole)-2- (5 Black-mouthed 3-Pyridinole) 1- 1-Methinorepropinole] — 2— (5 Trifluoromethyl 2 pyridyloxy) 2 Methylpropanamide, 3— {1 [Bis (4) -phenyl) methyl] azetidine-3--ylidene} 3— (3, 5-Difluorophenol) 2, 2 Dimethylpropane-tolyl, 1 {1 [1- (4 black-mouthed) pentyl] azetidine 3-yl} 1 (3,5 difluorophenol) 2 Methylpropane 2-ol, 3 -— ((S) — (4-Chlorophenyl) {3— [(lS) —l— (3,5-Difluorophenyl) 2-hydroxy 2-methylpro L] azetidine 1-yl} methyl) benzo-tolyl, 3 -— ((S) — (4-chlorophenol) {3— [(1S) —1 (3,5 difluorophenyl) 2-fluor-2-methylpropyl] Azetidine 1-yl} methyl) benzonitryl, 3— ((4 chlorophine) {3— [1— (3,5 difluorophenol) —2, 2 dimethylpropyl] azetidine-1-yl} methyl ) Benzo-tolyl, 3— ((1S) — 1— {1— [(S) one (3 cyanophyl) (4 cyanophyl) methyl] azetidine 3-yl} 2 fluoro 2 methylpropyl) 5 Fluorobenzo-tolyl, 3— [(S) — (4-chlorophenol) (3— {(13) —2—Fluoro 1 [3-Fluoro 5— (411 1, 2, 4-triazole 4 File) 2] methylpropyl} azetidine 1) methyl] benzol-tolyl, 5— ((4 cyanophyl) {3— [1— (3, 5 difluorophenol) 2-Fluoro-2-methylpropyl] azetidine— 1yl} methyl) thiophene—3—force lpo-tolyl, 3-— [(S) — (4-chlorophenol) (3— {(1S) — 2 fluoro-1 [3 — Fluoro-5— (5 oxo-4,5 dihydro 1, 3, 4 oxazodiazole 2-yl) phenol] — 2-methylpropyl} azetidine— 1-yl) methyl] benzo-tolyl, 3— [(S)-(4 Chlorophenyl) (3— {(1S) —2 Fluoro 1— [3 Fluoro 5— (1, 3, 4 Oxadiazol Luo 2 yl) Fuel] -2 Methylpropyl} Azetidine 1-yl) methyl] benzo-tolyl, 3-[(S)-(3— {(1S) — 1 [3— (5 amino-1, 3, 4-oxoxadiazole 1-yl) 5 fluorofe- 2] -Fluoro 1-methylpropyl} azetidine-1-yl) (4-phenyl) methyl] benzo-tolyl, 3 — [(S) — (4—Cyanophol) (3— {(IS) — 2 Fluoro 1— [3 Fluoro 5— (5—Oxo 4, 5 Dihydro 1, 3, 4, 4-Oxadiazo Luo 2-yl) phenol] — 2-methylpropyl} azetidine 1-yl) methyl] benzo-tolyl, 3— [(S) — (3— {(13) —1 [3— (5-aminomine 1, 3, 4 oxazodiazole 2-yl) 5 fluorophenyl] — 2 fluoro-2-methylpropyl} azetidine-1-yl) (4 cyanophyl) methyl] benzonitrile, ₃ [(s) Cyanophyl) (3— {(IS) — 2 Fluoro 1 [3 Fluoro 5— (1, 3, 4 Oxadiazol 2 yl) file] 2 Methylpropyl} azetidine-1 yl) methyl] benzo- Tolyl, 3— [(S) (4 —Black mouth) (3— {(1S) — 2 Fluoro 1— [3 Fluoro 5— (1, 2, 4—Oxaziazol 3 yl) 2] Methylpro L} azetidine 1-yl) methyl] benzonitrile, 3— [(1S) —1 (1 {(S) — (4 cyanophyl) [3— (1, 2, 4 oxazodiazole 3-yl) file ] Methyl} azetidine-3-yl) 2-Fluoro-2-methyl] 5 Fluorobenzoyl-tolyl, 5-— (3— {1— [1— (Diphenyl-dimethyl) azetidine 3-yl]-2-Fluoro 2 Methylpropyl} 5 Fluorophenyl) 1H—Tetrazole, 5 -— (3— {1 [1 (Diphenylmethyl) azetidin 1 yl] 2 Fluoro 2 Methylpropyl} 5 Fluorophenyl) 1 Methyl 1H— Tetrazole, 5— (3— {1 [1- (diphenylmethyl) azetidine-3-yl] 2 fluoro 2 methylpropyl} 5 fluorophenyl) -2 methyl 2 H-tetrazole, 3— [(4 ) (3— {2 Fluoro 1 [3 Fluoro 5— (2-Methyl-2H-tetrazole-5 yl) Ethyl] -2 Methylpropyl} azetidine— 1-yl) methyl] benzo-tolyl, 3— [(4-Chrome-Fuel) (3-— {2 Fluoro 1— [3 Fluoro 5— (1 Methyl-1H tetrazole 5 yl) phenol] — 2—methylpropyl} azetidine— 1—yl) methyl] benzo-tolyl, 3— [(4—cyanophyl) (3— {2 Fluoro 1 3 Fluoro 5— (1 Methyl 1H—tetrazol 5 yl) phenol] 2 Methylpropyl} azetidine 1 yl) Methyl] benzo-tolyl, 3— [(4-Cyanophyl) (3— {2 Fluoro 1- [3 Fluoro 5— (2-Methyl-2H-tetrazol-5-yl) phenol] -2 Methylpropyl} azetidine 1-yl) methyl] benzo-tolyl, 5-— {3— [(S) — {3— [(1S) — 1 Mo-5-fluorophenyl) -2-fluoro-2-methylpropyl] azetidine monoyl} (4-chlorophenyl) methyl] phenol} 1, 3, 4 oxadiazoluo 2 (3H) —on, 3— [(1S) —1 (1 {(S) — (4-Chlorophenyl) [3 -— (5 oxo 4,5 dihydro 1,3,4 oxazazol 2 yl) phenol] methyl} azetidine 3— 2) Fluoro-2-methylpropyl] 5 Fluorobenzo-tolyl, 3-— [(1S) — 1— (1— {(S) — (4 Xanophenol) [3— (5-Oxo 4, 5 Dihydro-1,3,4 oxadiazol 2 yl) phenol] methyl} azetidine 3 yl) 2 fluoro-2 methylpropyl] 5 fluo-benzoyl tolyl, 3 — [(IS) — 1— (1— {(S) 1 (4 cyanophyl) [3— (1, 3, 4 oxazodiazole 2 yl) file] methyl} azetidine 3 yl) 2 Fluoro 2 methylpropyl] 5 Fluoroben Zo-Tolyl, 3 — [(IS) — 1— (1— {(S) — (4 Chlorophenol) [3— (1, 3, 4-Oxadiazole 2-yl) phenol] methyl } Azetidine—3—yl) 2 Fluoro 2 methylpropyl] 5 Fluorobenzotolyl, 3 — ((1S) — 1 {1 [(S) — [3— (5 Amino 1, 3, 4 —Oxadiazole-2-yl) phenol] (4) Methyl] azetidine 3—yl} 2 fluoro-2-methylpropyl) 5 fluorobenzo-tolyl, 3— ((IS) — 1— { 1 — [(S) — [3— (5-amino-1,2,4-oxadiazol-2-yl) phenol] (4 cyanophyl) methyl] azetidine-3-yl} 2 fluoro-2-methyl Propyl) —5 Fluorobenzobenzotolyl, 3 — [(1S) — 1— (1 {(3) — (4-Shianophenol) [3— (1, 2, 4 oxazodiazole 3 yl) [Phenol] methyl} azetidine 3 yl) 2 fluoro-2-methylpropiyl ] 5 Fluorobenzol-tolyl, 3-[(13) -1- (1 {(3)-(4-Chlorophenol) [3- (1, 2, 4 Oxadiazole 3-yl)] ] Methyl} azetidine 3 yl) 2 Fluoro 2—Methylpropyl] — 5 Fluorobenzobenzoyl tolyl (IS) — 1— (3,5 Difluorophenol) —2 Fluoro-2-methylpropyl] azetidine— 1-yl} methyl) phenol] — 1, 3, 4-oxadiazole — 2 (3H) ON , 5— [3 — ((S) (4 chlorophenyl) {3— [(1S) — 1 3,5 difluorophenyl) 2-fluoro-2-methylpropyl] azetidine 1-yl} methyl) [Fail] -1, 3, 4-Oxadiazole-2 (311) -one, and 4 {(3) — {3— [(IS) —1— (3,5-Difluorophenol) —2-Fluoro-2-methylpropyl] azetidine 1-yl} [3— (5 oxo-4,5 dihydro-1,3,4-o A compound comprising: xadiazole —2-yl) phenol] methyl} benzo-tolyl.

[18] Obesity, diabetes, hormonal secretion abnormality, hyperlipidemia, gout, fatty liver, containing as an active ingredient the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof Metabolic diseases such as hepatitis and cirrhosis; angina pectoris, acute congestive heart failure, myocardial infarction, annular arteriosclerosis, hypertension, kidney disease and electrolyte abnormalities; bulimia, Affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit, hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormality, olfactory disorder, morphine tolerance, drug dependence Central and peripheral nervous system diseases represented by infectious diseases and alcoholism; reproductive system diseases represented by infertility, premature birth and sexual dysfunction; gastrointestinal diseases; respiratory diseases; preventive agents for cancer or skin pigmentation Or a therapeutic agent.

[19] The agent according to claim 18, which is a prophylactic or therapeutic agent for obesity.